Imidazopyridazine Compounds

ABSTRACT

The present invention relates to novel substituted imidazo[1,2-b]pyridazine compounds of Formula (I): pharmaceutical compositions thereof, and the use such compounds as corticotropin releasing factor 1 (CRF1) receptor antagonists in the treatment of psychiatric disorders and neurological diseases.

FIELD OF THE INVENTION

This invention relates to novel substituted imidazo[1,2-b]pyridazinecompounds, pharmaceutical compositions thereof, and the use of suchcompounds as corticotropin releasing factor 1 (CRF1) receptorantagonists in the treatment of psychiatric disorders and neurologicaldiseases.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland [J. Rivieret al., Proc. Natl. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al.,Science 213:1394 (1981)]. In addition to its endocrine role at thepituitary gland, immunohistochemical localization of CRF hasdemonstrated that the hormone has a broad extrahypothalamic distributionin the central nervous system and produces a wide spectrum of autonomic,electrophysiological and behavioral effects consistent with aneurotransmitter or neuromodulator role in the brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse in the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

There is evidence that CRF has a role in psychiatric disorders andneurological diseases including depression, anxiety-related disordersand feeding disorders. A role for CRF has also been postulated in theetiology and pathophysiology of Alzheimer's disease, Parkinson'sdisease, Huntington's disease, progressive supranuclear palsy andamyotrophic lateral sclerosis, as they relate to the dysfunction of CRFneurons in the central nervous system [for a review, see: E. B. DeSouze, Hosp. Practice 23:59 (1988)]. Furthermore, CRF is known to have abroad extrahypothalmic distribution in the CNS, contributing therein toa wide spectrum of autonomic behavioral and physiological effects [see,e.g., Vale et al., 1983; Koob, 1985; and E. B. De Souze et al., 1985].For example, CRF concentrations are significantly increased in thecerebral spinal fluid of patients afflicted with affective disorder ormajor depression [C. B. Nemeroff et al., Science 226:1342 (1984); C. M.Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al.,Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25:355(1989)]. Moreover, excessive levels of CRF are known to produceanxiogenic effects in animal models [see, e.g., Britton et al., 1982;Berridge and Dunn, 1986 and 1987]. The density of CRF receptors issignificantly decreased in the frontal cortex of suicide victims,consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch.Gen. Psychiatry 45:577 (1988)]. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (intravenously administered)observed in depressed patients [P. W. Gold et al., Am. J. Psychiatry141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Engl. J. Med. 314:1129 (1986)].Preclinical studies in rats and non-human primates provide additionalsupport for the hypothesis that hypersecretion of CRF may be involved inthe symptoms seen in human depression [R. M. Sapolsky, Arch. Gen.Psychiatry 46:1047 (1989)]. There is also preliminary evidence thattricyclic antidepressants can alter CRF levels and thus modulate thenumbers of receptors in the brain [Grigoriadis et al.,Neuropsychopharmacology 2:53 (1989)].

Neurochemical, endocrine and receptor binding studies have alldemonstrated interactions between CRF and benzodiazepine anxiolytics,providing further evidence for the involvement of CRF in thesedisorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRFboth in the conflict test [K. T. Britton et al., Psychopharmacology86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)]and in the acoustic startle test [N. R. Swerdlow et al.,Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptorantagonist Ro 15-1788, which was without behavioral activity alone inthe operant conflict test, reversed the effects of CRF in adose-dependent manner while the benzodiazepine inverse agonist FG 7142enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology94:396 (1988)]. Preliminary studies using the putative CRF receptorantagonist α-helical ovine CRF (9-41) in a variety of behavioralparadigms demonstrates that the antagonist produces “anxiolytic-like”effects that are qualitatively similar to the benzodiazepines [C. W.Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain ResearchReviews 15:71 (1990)].

CRF receptor subtypes, CRF1 and CRF2, have been identified and aredistributed heterogeneously within the brain [D. T. Chalmers et al.,TIPS 17:166-72 (1996)] thereby suggesting potential functional diversity[S. C. Heinrichs et al., Regul. Peptides 71:15 (1997)]. For example,widely distributed brain CRF1 receptors are strongly implicated inemotionality accompanying exposure to environmental stressors [G.Liebsch et al., Regul. Peptides 59: 229-39 (1995); D. W. Schulz, PNAS93: 10477-82 (1996)]. Significantly, CRF1, not CRF2, receptors appear tomediate select anxiogenic like behaviors [Heinrichs et al., 1997]. Amore discrete septal/hypothalmic distribution [D. T. Chalmers et al., J.Neurosci. 15(10): 6340-50 (1995)] and the availability of alternativeendogenous ligands [J. Vaughan et al., Nature 378: 287-92 (1995)]suggest an altogether different functional role for the CRF2 receptor[Heinrichs et al., 1997]. For example, a novel CRF-family neuropeptidewith preferential affinity for CRF2 relative to CRF1 receptors isreported to suppress appetite without producing the profile ofbehavioral activation observed with selective CRF1 agonism (H. Tezval etal., PNAS 101(25): 9468-9473 (2004)]. In many cases, CRF2 agonismproduces similar effects to those reported for CRF1 antagonists or CRF1gene deletion [S. C. Heinrichs, Trends in Pharmacological Sciences20(8):311-5 (1999)]. While CRF2 agonists have been proposed asantiobesity agents, CRF1 antagonists may be an important treatment forobesity as well [C. Contoreggi et al., Neuroendocrinology 80(2): 111-23(2004)].

In view of the above, efficacious and selective antagonists of CRF1 aredesired as potentially valuable therapeutic agents for the treatment ofpsychiatric disorders and neurological diseases. It is thus desirable todiscover new CRF1 antagonists.

SUMMARY OF THE INVENTION The compounds of the present invention includeCRF1 receptor antagonists. One embodiment of the present invention is acompound of Formula I:

wherein:

R⁰ is hydrogen, halo, methyl or ethyl;

R¹ and R³ are independently methyl, methoxy, or trifluoromethyl;

R² is selected from the group consisting of:

R⁴ is hydrogen, halo, or hydroxy;

R^(5a) and R^(5b) are independently ethyl or n-propyl;

R⁶ at each occurrence is independently hydrogen, halo, cyano,(C₁-C₄)alkyl, trifluoromethyl, methoxy, or phenyl;

R⁷ is hydrogen, halo, methyl, methoxy, dimethylamino,

R⁸ is selected from the group consisting of hydrogen, halo, cyano,(C₁-C₄)alkyl, R^(a)R^(b)N—, carbamyl, (C₁-C₂)alkoxy(C₁-C₂)alkyl,R¹¹—C(O)—,

R¹¹ is methoxy, methylamino, dimethylamino, or phenyl;

R¹² is hydrogen, halo, methyl, ethyl, trifluoromethyl, methoxy,trifluoromethoxy dimethylamino, acetyl, or methylsulfonyl;

R¹³ is hydrogen, methyl or halo;

R¹⁴ is hydrogen or hydroxy;

R¹⁵ is methylthio, cyclopropyl, phenyl,

R^(a) is hydrogen, (C₁-C₅)alkyl, (C₃-C₅)cycloalkyl, methoxy(C₂-C₄)alkyl,acetyl, (C₁-C₂)alkylsulfonyl, (C₃)alkenyl, R¹⁵—(CH₂)n-, or (C₁-C₂)alkylsubstituted with cyano, formyl, vinyl, or ethynyl;

R^(b) is hydrogen or (C₁-C₃)alkyl;

X is —CH₂—, —CO—, —O—, —S— or —SO₂—;

Y is —CH₂— or —O—;

z is S or O;

n is 1 or 2;

Q is hydrogen or methyl;

T is hydrogen or methyl;

J is methyl, trifluoroethyl, or tert-butyl; and

M is methyl or halo;

and pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is a compound of Formula Iwherein

R⁰ and R⁴ are hydrogen, R¹ and R³ are methyl, and R^(5a) and R^(5b) areethyl.

Yet another embodiment of the present invention is a compound of FormulaI wherein R² is selected from the group consisting of

where z is S.

A further embodiment of the present invention is a compound of Formula Iwherein R⁷ is hydrogen.

Another another embodiment of the present invention is a compound ofFormula I wherein R⁶ is halo or methyl.

Yet another embodiment of the present invention is a compound of FormulaI wherein R⁸ is

where X is O.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,diluent or excipient.

Yet another embodiment of the present invention is a compound of FormulaI, for use as a medicament.

A further embodiment of the present invention is use of a compound ofFormula I for the manufacture of a medicament for treating anxiety,depression, major depressive disorder, alcohol withdrawal symptoms, orirritable bowel syndrome in a mammal. In another further embodiment, themammal is a human.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

“Alkoxy” means an alkyl-O— group, wherein the alkyl group is as hereindescribed. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy,i-propoxy, and n-butoxy.

“Alkyl” means a saturated aliphatic hydrocarbon group, which may bestraight or branched, having 1 to 5 carbon atoms in the chain.

“Alkenyl” means an unsaturated aliphatic hydrocarbon group, which may bestraight or branched, having 2 to 4 carbon atoms in the chain.

“Cycloalkyl” means a monocyclic group, having 3 to 5 carbon atoms.

“Halo” means fluoro, chloro, bromo, or iodo.

“Pharmaceutically acceptable salts” refers to the relatively non-toxic,inorganic and organic acid addition salts, and base addition salts, ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds. Inparticular, acid addition salts can be prepared by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Exemplary acidaddition salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactiobionate, sulphamates, malonates,salicylates, propionates, methylene-bis-β-hydroxynaphthoates,gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like.See, for example S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm.Sci., 66, 1-19 (1977). Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing. Company, Easton,Pa., 1985, p. 1418.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts thereof.

“Therapeutically effective amount” or “effective amount” means theamount of the compound of formula I of the present invention orpharmaceutical composition containing a compound of formula I of thepresent invention that will elicit the biological or medical response ofor desired therapeutic effect on a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician.

The terms “treatment,” “treat,” “treating,” and the like, are meant toinclude both slowing or reversing the progression of a disorder. Theseterms also include alleviating, ameliorating, attenuating, eliminating,or reducing one or more symptoms of a disorder or condition, even if thedisorder or condition is not actually eliminated and even if progressionof the disorder or condition is not itself slowed or reversed. The term“treatment” and like terms also include preventive (e.g., prophylactic)and palliative treatment. Prevention of the disease is manifested by aprolonging or delaying of the onset of the symptoms of the disease.

The symbol “

” in a molecular structure indicates the position of attachment for thatparticular substituent.

When any variable occurs more than one time in any constituent or informula I, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. In choosing compounds of the present invention, one ofordinary skill in the art will recognize that the various substituents,i.e. R¹, R², etc., are to be chosen in conformity with well-knownprinciples of chemical structure connectivity.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, an arylcarbonylaminoalkyl substituent is equivalent toaryl-C(O)—NH-alkyl-.

The present invention contemplates specific classes of compounds ofFormula I. The following paragraphs describe such specific classes:

(a) R⁰ is hydrogen;(b) R¹ is methyl;(c) R³ is methyl;(d) R¹ and R³ are methyl;(e) R² is

(f) R² is

(g) R⁴ is hydrogen;(h) R^(5a) is ethyl;(i) R^(5b) is ethyl;(j) R^(5a) and R^(5b) are ethyl;(k) R⁶ is halo;(l) R⁶ is methyl;(m) R⁷ is hydrogen;(n) R⁸ is

(o) R⁸ is

While all the compounds of Formula I are useful CRF1 receptorantagonists, the following paragraphs describe further specific classes:

(a) Each of R¹ and R³ is methyl and each of R^(5a) and R^(5b) is ethyl;(b) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ ishydrogen;(c) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen;(d) R² is

and R⁷ is hydrogen;(e) R² is

R⁷ is hydrogen, and R⁶ is halo;

(f) R² is

R⁷ is hydrogen, and R⁶ is methyl;

(g) R² is

R⁷ is hydrogen, and R⁶ is halo or methyl, and R⁸ is

(h) R² is

and R⁶ is halo;(i) R² is

and R⁶ is methyl;(j) R² is

R⁶ is halo or methyl, and R⁸ is

(k) R² is

R⁶ is halo or methyl, and R⁸ is

The following paragraphs describe even more specific classes of CRF1receptor antagonists of the invention:

(a) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

is R⁷ is hydrogen, and R⁶ is halo or methyl, and R⁸ is

(b) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

is R⁷ is hydrogen, and R⁶ is halo, and R⁸ is

(c) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

is R⁷ is hydrogen, and R⁶ is methyl, and R⁸ is

(d) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

R⁶ is halo or methyl, and R⁸ is

(e) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

R⁶ is halo, and R⁸ is

(f) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

R⁶ is halo, and R⁸ is

(g) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

R⁶ is methyl, and R⁸ is

(h) R¹ and R³ are methyl, R^(5a) and R^(5b) are ethyl, and R⁰ and R⁴ arehydrogen, R² is

R⁶ is methyl, and R⁸ is

Preferably compounds of the invention exhibit a Ki value for CRF1binding of 1 micromolar or less, more preferably of 500 nanomolar orless. Even more preferably, compounds of the invention exhibit a Kivalue for CRF1 binding of 250 nanomolar or less, with 100 nanomolar orless being even further preferred. With even greater preference,compounds of the invention exhibit a Ki value for CRF1 binding of 30nanomolar or less, while 15 nanomolar or less is even more greatlypreferred. Compounds of the invention exhibiting a Ki value for CRF1binding of 5 nanomolar or less are most preferred.

The present invention also provides a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, diluent, orexcipient. A “pharmaceutically acceptable carrier, diluent, orexcipient” is a medium generally accepted in the art for the delivery ofbiologically active agents to mammals, e.g., humans. Such carriers aregenerally formulated according to a number of factors well within thepurview of those of ordinary skill in the art to determine and accountfor. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers and excipients include both aqueousand non-aqueous liquid media, as well as a variety of solid andsemi-solid dosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, well known to thoseof ordinary skill in the art. Descriptions of suitable pharmaceuticallyacceptable carriers, and factors involved in their selection, are foundin a variety of readily available sources, e.g., Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985.

These compounds of formula I may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles.

The pharmaceutical compositions containing compounds of general formulaI may be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Dosage forms suitable for administration generally contain from about 1mg to about 300 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition. Appropriate coatings may be applied toincrease palatability or delayed adsorption.

The compounds of formula I are antagonists at the CRF1 receptor and areuseful in the treatment of anxiety disorders, depression, majordepressive disorder, and stress related disorders. Anxiety disorders area group of diseases, recognized in the art, that includes phobicdisorders, anxiety states, post-traumatic stress disorder and atypicalanxiety disorders [The Merck Manual of Diagnosis and Therapy, 16thedition (1992)]. Emotional stress is often a precipitating factor inanxiety disorders, and such disorders generally respond to medicationsthat lower response to stress. The compounds are also useful in smokingcessation programs. The method of treatment involves administration to amammal (e.g. a human) an effective amount of a compound of theinvention. In particular, therapeutically effective amounts of thecompounds of this invention are amounts effective to antagonize, orlower, levels of corticotropin releasing factor (CRF) in a mammal (e.g.a human), thereby alleviating in the mammal's conditions characterizedby abnormally high levels of CRF expression.

As such, the present invention provides a method for treating acondition which is treatable by reducing CRF1 receptor stimulation,comprising administering to the mammal (e.g. a human) in need thereof acompound of Formula I, or a pharmaceutically acceptable salt thereof, inan amount effective to antagonize CRF1 receptor stimulation.

The present invention also provides use of a compound of Formula I forthe manufacture of a medicament for treating a condition which istreatable by reducing CRF1 receptor stimulation.

The present invention also provides a method of antagonizing CRF1receptors in a warm-blooded animal, comprising administering to theanimal a compound of the invention at amount effective to antagonizeCRF1 receptors. The warm-blooded animal is preferably a mammal, and morepreferably a human.

The present invention also provides a method of treating a disorder in awarm-blooded animal, which disorder manifests hypersecretion of CRF, orthe treatment of which disorder can be effected or facilitated byantagonizing CRF1 receptors, comprising administering to the animal atherapeutically effective amount of a compound of the invention. Thewarm-blooded animal is preferably a mammal, and more preferably a human.

Compounds of Formula I, or a pharmaceutically acceptable salt thereof,are useful for treating various disorders and conditions in a mammal(e.g. human) including social anxiety disorder; panic disorder;obsessive-compulsive disorder; major depressive disorder; anxiety withco-morbid depressive illness; affective disorder; anxiety; depression;irritable bowel syndrome; post-traumatic stress disorder; supranuclearpalsy; immune suppression; gastrointestinal disease; anorexia nervosa,bulimia, or other feeding disorder; drug or alcohol withdrawal symptoms;substance abuse disorder (e.g., nicotine, cocaine, ethanol, opiates, orother drugs); inflammatory disorder; fertility problems; disorders thetreatment of which can be effected or facilitated by antagonizing CRF,including but not limited to disorders induced or facilitated by CRF; adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; sleep disorders induced by stress; stress-related illnesses;pain perception such as fibromyalgia; mood disorders such as depression,including major depression, major depressive disorder, single episodedepression, recurrent depression, child abuse induced depression, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;fatigue syndrome; chronic fatigue syndrome; stress-induced headache;headache; cancer; human immunodeficiency virus (HIV) infections;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, Huntington's disease, senile dementia of the Alzheimer's type,and multiinfarct dementia; gastrointestinal diseases such as ulcers,irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, andpost operative ilius and colonic hypersensitivity associated bypsychopathological disturbances or stress; eating disorders such asanorexia and bulimia nervosa; hemorrhagic stress; stress-inducedpsychotic episodes; euthyroid sick syndrome; syndrome of inappropriateantidiarrhetic hormone (ADH); obesity; obesity and the metabolicsyndrome; infertility; premature birth; head traumas; spinal cordtrauma; ischemic neuronal damage (e.g., cerebral ischemia such ascerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy;cardiovascular and heart related disorders including hypertension,tachycardia and congestive heart failure; stroke; immune dysfunctionsincluding stress induced immune dysfunctions (e.g., stress inducedfevers, stress induced infections in humans and animals, porcine stresssyndrome, bovine shipping fever, equine paroxysmal fibrillation, anddysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; chemicaldependencies and addictions (e.g., dependences on alcohol, cocaine,heroin, benzodiazepines, or other drugs); drug and alcohol withdrawalsymptoms; osteoporosis; psychosocial dwarfism and hypoglycemia.

A compound of this invention can be administered to treat the abovedisorders or abnormalities by means that produce contact of the activeagent with the agent's site of action in the body of a mammal (e.g.human), such as by oral or parenteral administration using appropriatedosage forms. The compounds can be administered by any conventionalmeans available for use in conjunction with pharmaceuticals either asindividual therapeutic agent or in combination of therapeutic agents. Itcan be administered alone, but will generally be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The therapeutically effective amounts of the compounds of the inventionfor treating the diseases or disorders described above in a warm-bloodedanimal can be determined in a variety of ways known to those of ordinaryskill in the art, e.g., by administering various amounts of a particularagent to an animal afflicted with a particular condition and thendetermining the effect on the animal. Typically, therapeuticallyeffective amounts of a compound of this invention can be orallyadministered daily at a dosage of the active ingredient of 0.002 to 200mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divideddoses one to four times a day, or in sustained release formulation willbe effective in obtaining the desired pharmacological effect. It will beunderstood, however, that the specific dose levels for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular disease.Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most CNSdisorders, a dosage regimen of four-times daily or less is preferred.For the treatment of stress and depression, a dosage regimen of one ortwo-times daily is particularly preferred.

It will be appreciated that all combinations of specific and preferredembodiments discussed above and the examples discussed below arecontemplated as being encompassed by the present invention, providedsuch combinations do not comprise inconsistent groupings. In addition,all examples described herein are for illustrative purposes, and are notintended to narrow the scope of the invention in any way.

Compounds of the invention can generally be prepared using the syntheticroutes illustrated in the Schemes below. Starting materials can beprepared by procedures described in these schemes or by procedures thatwould be well known to one of ordinary skill in organic chemistry. Thevariables used in the schemes are as defined below or as in the claims.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula I. Thepresent invention contemplates all enantiomers and mixtures ofenantiomers and stereoisomers, that is, both the stereomerically pureform (e.g., geometrically pure, enantiomerically pure, ordiastereomerically pure) and enantiomeric and stereoisomeric mixtures,including racemates. Enantiomeric and stereoisomeric mixtures can beresolved into their component enantiomers or stereoisomers by well knownmethods, such as chiral phase gas chromatography, chiral-phase highperformance liquid chromatography, or crystallizing the compound as achiral salt complex. Enantiomers and stereoisomers can also be obtainedfrom stereomerically- or enantiomerically-pure intermediates, reagents,and catalysts by well known asymmetric synthetic methods.

Pharmaceutically acceptable salts are contemplated to be within thescope of the present invention. The compounds of the present inventionare bases and salts of such compounds may be formed with acids, forexample, a salt with inorganic acid such as hydrochloric acid or a saltwith organic acid such as trifluoroacetic acid.

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. These schemes, therefore, are not limited bythe compounds listed nor by any particular substituents employed forillustrative purposes.

In Scheme I, a substituted 3-amino-pyridazine 1 is acylated withpivaloyl halide and a base, e.g., triethylamine in a polar aproticsolvent, e.g., methylene chloride at from room temperature to the refluxto give amide 2. Amide 2 is treated with a Grignard reagent indiethylether or THF to give the 4-substituted amide 3. Amide 3 ishydrolyzed with aqueous HCl at from room temperature to 110° C. thenneutralized to provide free amine 4. Amine 4 is treated with analpha-halo ketone and base, e.g., sodium bicarbonate in 95% ethanol atfrom room temperature to 110° C. to give imidazopyridazine 5.Imidazopyridazine 5 is treated with a halogenating reagent e.g., N-iodoor N-bromosuccinimide in a polar aprotic solvent (e.g., acetonitrile) atfrom 0° C. to room temperature to give halide 6. Halide 6 undergoeshalogen metal exchange with an alkyl lithium reagent, e.g., n-, sec-, ortert-butyllithium in diethylether or THF at from −78° C. to roomtemperature, followed by treatment with a trialkylborate, e.g.,trimethylborate to give an intermediate boronic ester, which ishydrolyzed upon workup with aqueous HCl to provide boronic acid 7.

In Scheme II equation 1, halide 6 can be used in a coupling reactionwith a 5-membered ring heterocyclic boronic acid 8 in the presence ofpalladium catalysis, e.g., tetrakis-triphenylphosphine palladium (0) ina lower alkanol (methanol or n- or i-propanol)/DME mixture at from70-120° C. to give compounds of formula I.

Alternately in equation 2, boronic acid 7 can be used in a couplingreaction with a 5 membered ring heterocyclic halide 9 and palladiumcatalysis, e.g., tetrakis-triphenylphosphine palladium (0) in a loweralkanol (methanol or n- or i-propanol)/DME mixture at from 70-120° C. togive a compound of formula I.

In equation 3, 5-membered ring heterocyclic halides 9 may undergohalogen-lithium exchange with, e.g., n-, sec- or tert-butyl lithium inTHF or ether at −65° C., followed by lithium-zinc exchange with ZnCl₂ ineither diethylether or THF at temperatures up to room temperature. Thein situ organozinc reagent 10 may then undergo coupling with halide 6 inthe presence of palladium, e.g., PdCl₂(dppf) in THF at from 70-120° C.to give a compound of formula I.

In equation 4, a 5-membered heterocyclic ring with a ring proton may belithiated by either an alkyllithium, e.g., n-, sec- or tert-butyllithium or lithium diisopropyl amide in THF or ether at −65° C. to roomtemperature followed by lithium-zinc exchange with anhydrous zinc halidein either diethylether or THF to give an organozinc reagent 10 that isused as in equation 3 above. One skilled in the art will also appreciatethat commercially available organozinc reagents 10 can be used directlyas an organozinc coupling partner.

Furthermore from equation 5, it may be advantageous or convenient to useReike Zn in THF to directly convert a 5-membered ring heterocyclichalide 9 to an organozinc reagent 10 for coupling with a halide 6.

In equation 6, a 5 membered heterocyclic halide 9 can be directlycoupled with the imidazo[1,2-b]pyridazine intermediate 5 in the presenceof palladium, e.g., Pd₂(dba)₃, PdCl₂, Palladium acetate/TDBPP, ortetrakis-triphenylphosphine palladium (0) in DMF, THF, or NMP solventfrom 70-120° C. to give a compound of formula I.

Alternately, from equation 7, the imidazo[1,2-b]pyridazine halide 6 maybe directly coupled with a 5 membered heterocycle 11 in the presence ofpalladium, e.g., Pd₂(dba)₃, PdCl₂ or Palladium acetate/TDBPP in DMF,THF, or NMP solvent from 70-120° C. to give a compound of formula I.

Several 5 membered heterocyclic rings and/or their bromides and/oriodides useful as starting materials for the synthesis of compounds ofFormula I are commercially available or may be prepared by methods wellknow to the skilled artisan. From Scheme III, they may also be preparedby halogenation, e.g., with bromine, NBS or NIS. Furthermore, some ofthe intermediates 11 and 12 may be prepared by lithium halogen exchangefollowed by water quench.

Compounds of Formula I as intermediates in the preparation of othercompounds of Formula I include the addition of aryllithium reagents(generated by the methods of equations 3 and 4 in Scheme II) to carbonylcompounds, e.g., aldehydes, ketones, esters, and Weinreb amides. Theresulting carbinols or carbonyl compounds are further elaborated byhalogenation under acidic conditions and by a second aryllithiumaddition, respectively.

Abbreviations TBDMSCl or TBDMSiCl—tert-butyl-dimethylsilyl chloride MS(ES)—Electrospray Mass spectrum THF—tetrahydrofuranDMSO—Dimethylsulfoxide DMF—Dimethylformamide DCM, CH2Cl2—dichloromethaneDioxane—1,4-dioxane N2—nitrogen gas NIS—N-iodosuccinimideNBS—N-bromosuccinimide MeOH—methanol EtOH—95% ethanol RBF, RB—roundbottom flask RBSN—round bottom single neck flask SiO2—silica gel EtOAc,AcOEt—ethylacetate GFF—glass microfiber filter HPLC—high pressure liquidchromatography on silica gel ISCO—ISCO brand low pressure liquidchromatography on silica gel AcCl—acetyl chloride LDA—lithiumdiisopropylamine KOAc—Potassium Acetate TBABr—Tetrabutyl ammoniumbromide NMP—N-Methylpyrrolidinone TDBPP—Tris (2,4-di-t-butylphenyl)phosphite. Pd₂ dba₃—Tris(dibenzylideneacetone)dipalladiumPdCl₂(dppf)—Dichloro(diphenylphosphinoferrocene)palladiumTetrakis—tetrakis-(triphenylphosphine)-palladiumDppf—1,1′-bis(diphenylphosphino)ferrocene)

r.t., RT—room temperature

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following examples are provided to describe theinvention in further detail. They are intended to illustrate and not tolimit the invention in any way whatsoever. Examples 1-255 provideexemplary compounds and illustrate the preparation thereof. Examples A-Dillustrate various biological assays that can be used for determiningthe biological properties of the compounds of the inventions. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures described in the examples.

Example 1 Preparation of8-(1-ethyl-propyl)-3-(2,4-dimethyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 6-Methyl-pyridizin-3-ylamine

3-Chloro-6-methylpyridazine (25.0 g, 0.229 moles) is dissolve in 250 mLof NH₄OH and heated to 170° C. in a sealed container for 24 hours. Thesolvents are evaporated. The residue is triturated in methylenechloride, and a solid is filtered. This trituration procedure isrepeated with the filtrate four times. The filtered solids are combinedand dried in a vacuum oven overnight to obtain the title compound as anoff-white solid 4.32 g (0.040 moles, 20%). ¹H-NMR (dmso-d6): δ 7.1 (d,J=8.9 Hz, 1H); 6.67 (d, J=8.9 Hz, 1H); 6.04 (s, br, 2H); 2.33 (s, 3H)ppm. ES+=110 (100%, M+1).

B. 2,2-Dimethyl-N-(6-methyl-pyridazine-3-yl)-propionamide

Method 1: To a dry flask is added 7.12 g (0.065 mole) of6-methyl-pyridizin-3-ylamine in 170 ml dry methylene chloride. Next,14.5 ml of triethylamine is added and the reaction is cooled to 0° C.Pivaloyl chloride (2.7 ml, 1.2 eq) is carefully added, and the reactionmixture is stir 10 minutes, removed from the bath, and stirred 4 hoursmore. Dichloromethane (200 mL) is added, and the reaction mixture iswashed 3 times with saturated aqueous sodium bicarbonate, then brine.The organic layer is dried over sodium sulfate, filtered, and evaporatedto an oil. The crude product is purified via silica gel chromatographyusing a hexane:ethyl acetate gradient giving the title compound as awhite solid weighing 1.51 g (7.8 mmoles, 42.7%). ¹H-NMR (DMSO-d₆), δ10.39 (s, 1H); 8.11 (d, J=9.30 Hz, 1H); 7.51 (d, J=9.29 Hz, 1H); 2.54(s, 3H); 1.23 (s, 9H) ppm. ES⁺=194 (M+1).

Method 2: To a dry pressure tube is added 200 mg (1.56 mol) of3-chloro-5-methylpyridazine, 190 mg (1.87 mmol) of trimethylacetamide,14.6 mg (0.023 mmol) of rac-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl,tris(dibenzylideneacetone)-dipalladium (0), 762.4 mg (2.34 mmol) ofcesium carbonate and 1.5 ml dry tetrahydrofuran. The pressure tube ispurged with nitrogen and sealed. The reaction is heated to 100° C.overnight. The reaction is then cooled, diluted with dichloromethane,and filtered through celite. Solvents are evaporated and the crudeproduct is purified via silica gel chromatography using a ethylacetate:hexane gradient to obtain 91 mg (0.47 mmol, 30%) as a whitesolid.

C.N-[4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide

Activated magnesium powder (19.2 g, 0.792 moles) is added to a dry 3 Lflask fitted with a condensor and a drop funnel. The entire apparatus isheated with a gun dry under vacuum and allowed to cool. Enough ether isadded to cover the magnesium. 3-Bromopentane (100 g, 0.662 mmol) isadded to the addition funnel in 175 ml of diethyl ether. A ⅓ of thebromopentane solution is added to the magnesium and the reaction mixtureis stirred under nitrogen until bubbling occurs. Then, the rest isdripped in at such a rate that the bubbling continues gently. Thereaction is stirred for 30 minutes after bubbling ceases. Next,2,2-dimethyl-N-(6-methyl-pyridazine-3-yl)-propionamide (21.3 g, 0.110mmol) dissolved in 225 ml of dry THF is added dropwise. The reactionmixture is stirred for 1 hour. Saturated sodium tartrate (1 L) iscarefully added, and the reaction is stirred for 30 minutes. Thereaction mixture is transferred to a larger flask, 2 L of ethyl acetateis added, and the reaction is stirred 1 hour more. The layers areseparate and the aqueous layer is extracted several times with ethylacetate. The organic extracts are combined, and the solvents areevaporated. The residue is taken up in 600 mL of dichloromethane, andiodine (28 g, 0.110 mol) is added. The reaction is stirred for 2 hours.The organic layer is washed once with aqueous solution of sodium sulfiteand then with water. The organic layer is dried over sodium sulfate,filtered, and evaporated to red oil. The crude product is purified viasilica gel chromatography using a hexanes:ethyl acetate gradient. Theproduct fractions are combined and evaporated. The residue is trituratedin ethyl acetate and a light tan solid is filtered to obtain 12.0 g(45.6 mmol, 41%) of the title compound. ¹H-NMR (DMSO-d₆), δ 9.88 (s,1H); 7.59 (s, 1H); 2.60 (s, 3H); 2.39-2.42 (m, 1H); 1.21-1.37 (m, 2H);1.38-1.43 (m, 2H); 1.23 (s, 9H); 0.71 (t, J=7.49 Hz, 6H) ppm.MS/ES⁺=264.

D. 4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-ylamine

N-[4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide(12.0 g, 45 mmol) is dissolved in 60 mL of concentrated hydrochloricacid. The reaction mixture is heated to 95° C. in a sealed flask for 2hours. The reaction is worked up by pouring over ice and extracting withethyl acetate three times. The organic layer is discarded, and the pH ofthe aqueous layer is adjusted using 2 N sodium hydroxide. The basicsolution is extracted with ethyl acetate five times. The organicextracts are combined, dried over magnesium sulfate, filtered, andevaporated to obtain 6.68 g (37 mmol, 81%) of the title compound as abrownish oil. ¹H-NMR (DMSO-d₆), δ 6.95 (s, 1H); 5.89 (s, br, 2H);2.52-2.56 (m, 1H); 2.34 (s, 3H); 1.44-1.58 (m, 4H); 0.72 (t, J=7.04 Hz,6H) ppm. MS/ES⁺=180 (100%, M+1).

E. 8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

4-(1-Ethyl-propyl)-6-methyl-pyridazin-3-ylamine (850 mg, 4.74 mmol),chloroacetone (0.415 ml, 5.22 mL) and 20 mL of ethanol are heated in themicrowave at 110° C. for 35 minutes. Sodium bicarbonate (1.2 g, 14.2mmol) is added, and the reaction mixture is heated in an oil bath at100° C. overnight. The solvent is evaporate and the residue is taken upin ethyl acetate and washed three times with brine. The organic layer isdried over sodium sulfate, filtered, and evaporated to a brown oil. Thecrude product is purified via silica gel chromatography using ahexane:ethyl acetate gradient. The title compound is an oil weighing3.69 g (17.0 mmol, 84%). ¹H-NMR (DMSO-d₆), δ 7.34 (s, 1H); 6.84 (s, 1H);2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712(t, J=7.49 Hz, 6H) ppm. MS/ES⁺=219 (100%, M+2).

F. 8-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (5.1 g, 0.023moles) and 50 mL of dry acetonitrile are added to a nitrogen purgedflask and are cooled to 0° C. NIS (5.54 g, 0.025 moles) in 90 mL of dryacetonitrile is added. The bath is allowed to come to room temperature,and the reaction to stir overnight. The solvents are evaporated. Theresidue is taken up in ethyl acetate, washed two times with 50% aqueoussolution of sodium thiosulfate and with brine. The organic layer isdried over sodium sulfate, filtered, and evaporated to a residue again.The crude product is triturated in a small amount of acetonitrile, and asolid is filter off. The trituration is repeated several times to obtainthe title compound as a light tan solid weighing 7.29 g (0.021 moles,91%). ¹H-NMR (DMSO-d₆), δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H);2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES⁺=344(100%, M+1).

G. 8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-3-yl boronicacid

In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 1.00 g(2.91 mmol) of8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine in 60 mLof dry THF is cooled to −78° C. 4.12 mL (7.00 mmol) of 1.7 Mtert-butyllithium in hexanes is added and reaction is stirred at −78° C.for 1 hour. 0.818 mL (7.30 mmol) of trimethyl borate is added andreaction is followed by MS and TLC (1:1 Hexane:EA) Indication of productis observed by mass spectrum. The reaction is allowed to stir for anadditional hour, quenched with 1 N hydrochloric acid, and diluted withethyl acetate. The organic layer is separated, and the aqueous layer isextracted three times with 100 mL of ethyl acetate. The extracts arecombined, dried over MgSO₄, filtered, and concentrated. The reactionresidue is triturated in hexanes and a solid is filter off. MS,ES⁺=262.2 (M+1).

H.8-(1-Ethyl-propyl)-3-(2,4-dimethyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a microwave pressure tube is added 0.340 g (1.30 mmol) of8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-3-yl boronicacid, 0.100 g (0.521 mmol) of 5-bromo-2,4-dimethylthiazole, 0.361 g(0.313 mmol) of Pd(PPh₃)₄, 0.650 mL (1.30 mmol) of 2 M aqueous Na2CO3,and 2 mL 7:3:2 DME:H2O:EtOH, and the mixture is heated at 160° C. for 40min. Reaction is checked by MS which indicates product present. Thereaction mixture is partitioned between 75 mL of ethyl acetate and 75 mLof water. The layers are separated and the aqueous is extracted 3×50 mLof ethyl acetate, dried (MgSO4), and concentrated under vacuum. Thecrude mixture is purified by chromatography using hexanes/ethyl acetateas a solvent system. The product containing fractions are combined toobtain 0.100 g of the product, 58% yield. MS, ES+=329.2 (M+1); ¹H-NMR(DMSO-d6)=6.974 (s, 1H); 3.085-3.052 (m, 1H); 2.665 (s, 3H); 2.438 (s,3H); 2.290 (s, 3H); 2.147 (s, 3H); 1.849-1.727 (m, 4H); 0.776-0.738 (m,6H) ppm.

Example 2 Preparation of8-(1-ethyl-propyl)-3-(2-ethyl-4-methyl-5-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 5-Bromo-2-ethyl-4-methylthiazole

In an oven dried, N₂ purged, 50 mL round bottom flask, 1.00 g (7.86mmol) of 2-ethyl-4-methylthiazole is reacted with 0.487 mL (9.43 mmol)of bromine in 7 mL of acetic acid at room temperature. Reaction ischecked by MS after 2 hours. The reaction mixture is partitioned between50 mL H₂O and 25 mL of CH₂Cl₂. The layers are separated and the aqueousis extracted 3×25 mL of CH₂Cl₂. The organics are combined and washed1×25 mL 1N Na₂S₂O₃, dried (MgSO₄), and concentrated under vacuum to give1.38 g of the title compound, 85% yield. MS, ES+=206.0 (M+1); ¹H-NMR(DMSO-d6)=2.940-2.810 (m, 2H); 2.253-2.251 (m, 3H); 1.225-1.222 (m, 3H)ppm.

B.8-(1-Ethyl-propyl)-3-(2-ethyl-4-methyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 1H,5-bromo-2-ethyl-4-methylthiazole produces the title product in 27%yield. MS, ES+=343.2 (M+1); ¹H-NMR (DMSO-d6)=6.975 (s, 1H); 3.090-3.056(m, 1H); 3.025-2.968 (m, 2H); 2.439 (s, 3H); 2.291 (s, 3H); 2.155 (s,3H); 1.835-1.744 (m, 4H); 1.338-1.300 (m, 3H); 0.776-0.740 (m, 6H) ppm.

Example 3 Preparation of8-(1-ethyl-propyl)-3-(2-isopropyl-4-methyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 5-Bromo-2-isopropyl-4-methylthiazole

Using a procedure similar to Example 2A, 2-isopropyl-4-methylthiazoleproduces the title product in 90% yield. MS, ES+=220.0 (M+1); ¹H-NMR(DMSO-d6)=3.210-3.175 (m, 1H); 2.257 (s, 3H); 1.264-1.248 (d, 6H) ppm.

B.8-(1-Ethyl-propyl)-3-(2-isopropyl-4-methyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 1H,5-bromo-2-isopropyl-4-methylthiazole produces the title product in 29%yield. MS, ES+=357.2 (M+1); ¹H-NMR (DMSO-d6)=6.990 (s, 1H); 3.120-3.050(m, 1H); 2.442 (s, 3H); 2.294 (s, 3H); 2.158 (s, 3H); 1.810-1.750 (m,4H); 1.362-1.344 (d, 6H); 0.777-0.741 (m, 6H) ppm.

Example 4 Preparation of8-(1-ethyl-propyl)-3-(4-methyl-2-phenyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 5-Bromo-4-methyl-2-phenylthiazole

Using a procedure similar to Example 2A, 4-methyl-2-phenylthiazoleproduces the title product in 90% yield. MS, ES+=256.0 (M+1); ¹H-NMR(DMSO-d6)=7.900-7.867 (m, 2H); 7.538-7.512 (m, 3H); 2.407 (s, 3H) ppm.

B.8-(1-Ethyl-propyl)-3-(4-methyl-2-phenyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 1H,5-bromo-4-methyl-2-phenylthiazole produces the title product in 24%yield. MS, ES+=391.3 (M+1); ¹H-NMR (DMSO-d6)=8.005-7.995 (m, 2H);7.538-7.534 (m, 3H); 7.010 (s, 1H); 3.185-3.095 (m, 1H); 2.496 (s, 3H);2.394 (s, 3H); 2.316 (s, 3H); 1.895-1.785 (m, 4H); 0.826-0.788 (m, 6H)ppm.

Example 5 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(2-methyl)propyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 5-Bromo-4-methyl-2-(2-methyl)propylthiazole

Using a procedure similar to Example 2A,4-methyl-2-(2-methyl)propylthiazole produces the title product in 96%yield. MS, ES+=234.1 (M+1); ¹H-NMR (DMSO-d6)=2.744 (m, 2H); 2.259 (s,3H); 1.895-2.000 (m, 1H); 0.905-0.888 (m, 6H) ppm.

B.8-(1-Ethyl-propyl)-3-(4-methyl-2-(2-methyl)propyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 1H,5-bromo-4-methyl-2-(2-methyl)propylthiazole produces the title productin 7% yield. MS, ES+=371.3 (M+1); ¹H-NMR (DMSO-d6)=7.013 (s, 1H); 3.109(m, 1H); 2.892-2.875 (d, 2H); 2.517 (s, 3H); 2.513 (s, 3H); 2.476 (s,3H); 2.107-2.073 (m, 1H); 1.868-1.780 (m, 4H); 1.018-1.002 (d, 6H);0.813-0.775 (m, 6H) ppm.

Example 6 Preparation of8-(1-Ethyl-propyl)-3-[4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

3.00 g of8-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (8.74mmol), 4.32 g of 4-methyl-2H-thiazole (43.6 mmol), 453 mg oftriphenylphosphine (1.73 mmol) and 5.85 g of cesium carbonate (18.0mmol) are placed into the sealed tube with 20 ml of DMF and N2 gas isbubbled in for 40 min. 39 mg of Pd2 dba3 (0.43 mmol) is added and thetube is sealed and heated at 130° C. overnight. The cooled reactionmixture is filtered and applied onto silica-gel column(Hexane→Hexane:AcOEt=3:1) to give 2.12 g of the title compound (77%).¹H-NMR (DMSO-d6) δ 9.215 (s, 1H); 6.993 (s, 1H); 3.079 (m, 1H); 2.480(s, 3H); 2.439 (s, 3H); 2.302 (s, 3H); 1.824-1.751 (m, 4H); 0.780-0.743(m, 6H) ppm. MS, ES+=315.2.

Example 7 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-2-pyridin-2-yl-thiazol-5-yl)-imidazo[1,2-b]pyridazine

A.8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

In an oven dried, N2 purged, 15 mL round bottom flask, 0.028 g (0.089mmol) of8-(1-ethyl-propyl)-3-[4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine.in 1.5 mL of dry CH₂Cl₂ is cooled to 0 C. 0.019 g (0.107 mmol) of NBS isadded and reaction is stirred overnight allowing bath to come to roomtemperature. Reaction mixture is directly purified by chromatographyusing hexane/ethyl acetate as solvent system. The product containingfractions are combined to obtain 0.012 g, 34% yield. MS, ES+=395.1(M+1); ¹H-NMR (DMSO-d6)=7.070 (s, 1H); 3.10 (m, 1H); 2.49 (s, 3H); 2.36(s, 3H); 2.25 (s, 3H); 1.85-1.78 (m, 4H); 0.81-0.77 (m, 6H) ppm.

B.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(4-methyl-2-pyridin-2-yl-thiazol-5-yl)-imidazo[1,2-b]pyridazine

A mixture of3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(380 mg, 0.96 mmol), 2-pyridinezinc bromide (0.5 M in THF, 2.1 mL, 4mmol), Pd(PPh₃)₄ (30 mg, 0.026 mmol) and THF (3 mL) is heated at 80° C.for 18 hours. Ethyl acetate (20 mL) is added. The organic layer isseparated, dried over magnesium sulfate, filtered, and the solventremoved in vacuo. Purification is performed via silica gelchromatography using a 3:1 mixture of hexanes and ethyl acetate aseluent to produce the title compound 325 mg (86%). ¹H-NMR (CDCl₃), δ9.55 (m, 1H); 8.10 (m, 1H); 7.73 (m, 1H); 7.26 (m, 1H); 6.58 (s, 1H);3.24 (m, 1H); 2.43 (s, 3H); 2.40 (s, 3H); 2.33 (s, 3H); 1.76 (m, 4H);0.80 (t, 6H) ppm. MS/ES⁺=391 (100%, M+1).

Example 8 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(3-pyridyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a microwave pressure tube is added 0.070 g (0.178 mmol) of8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine,0.066 g (0.534 mmol) of pyridine-3-boronic acid, 0.103 g (0.089 mmol) ofPd(PPh3)4, 0.267 μL (0.534 mmol) of 2 M aqueous Na2CO3, and 1 mL 7:3:2DME:H2O:EtOH, and the mixture is heated at 160° C. for 60 min. Thereaction mixture is partitioned between 25 mL of ethyl acetate and 25 mLof water. The layers are separated and the aqueous is extracted 3×25 mLof ethyl acetate, dried (MgSO4), and concentrated under vacuum. Thecrude mixture is purified by chromatography using hexanes/Ethyl acetateas a solvent system. The product containing fractions are combined toobtain 0.045 g of the product, 64% yield. MS, ES+=392.2 (M+1); ¹HNMR(DMSO-d6) δ 9.18 (s, 1H); 8.65 (m, 1H); 8.34 (d, 1H); 7.60 (m, 1H); 7.06(s, 1H); 3.06 (m, 1H); 2.50 (s, 3H); 2.40 (s, 3H); 2.34 (s, 3H);1.87-1.82 (m, 4H); 0.83-0.79 (m, 6H) ppm.

Example 9 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(4-pyridyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, pyridine-4-boronic acid producesthe title compound in 10% yield. MS, ES+=392.3 (M+1); ¹HNMR(DMSO-d6)=8.79 (s, 2H); 7.80 (m, 2H); 7.07 (s, 1H); 3.12 (m, 1H); 2.50(s, 3H); 2.40 (s, 3H); 2.36 (s, 3H); 1.90-1.80 (m, 4H); 0.83-0.79 (m,6H) ppm.

Example 10 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(thiophene-2-yl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, thiophene-2-boronic acidproduces the title compound in 89% yield. MS, ES+=397.1 (M+1); ¹H-NMR(DMSO-d6)=7.81-7.79 (d, 1H); 7.78-7.77 (d, 1H); 7.21-7.20 (m, 1H); 7.05(s, 1H); 3.19-3.15 (m, 1H); 2.50 (s, 3H); 2.39 (s, 3H); 2.27 (s, 3H);1.85-1.83 (m, 4H); 0.82-0.79 (m, 6H) ppm.

Example 11 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(2-fluorophenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 2-fluorophenyl boronic acidproduces the title compound in 82% yield. MS, ES+=409.2 (M+1); ¹H-NMR(DMSO-d6)=8.32-8.28 (m, 1H); 7.60-7.58 (m, 1H); 7.57-7.41 (m, 2H); 7.05(s, 1H); 3.13-3.12 (m, 1H); 2.49 (s, 3H); 2.40 (s, 3H); 2.35 (s, 3H);1.91-1.780 (m, 4H); 0.87-0.79 (m, 6H) ppm.

Example 12 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(4-fluorophenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 4-fluorophenyl boronic acidproduces the title compound in 63% yield where the crude mixture ispurified by chromatography using 2% methanol in dichloromethane as asolvent system. MS, ES+=409.2 (M+1); ¹H-NMR (DMSO-d6)=8.06-8.03 (m, 2H);7.408-7.36 (m, 2H); 7.05 (s, 1H); 3.14-3.11 (m, 1H); 2.50 (s, 3H); 2.39(s, 3H); 2.31 (s, 3H); 1.90-1.78 (m, 4H); 0.83-0.79 (m, 6H) ppm.

Example 13 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(3-fluorophenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 3-fluorophenyl boronic acidproduces the title compound in 77% yield where the crude mixture ispurified by chromatography using 2% methanol in dichloromethane as asolvent system. MS, ES+=409.2 (M+1); ¹H-NMR (DMSO-d6)=7.84-7.78 (m, 2H);7.64-7.57 (m, 2H); 7.41-7.36 (m, 1H); 7.06 (s, 1H); 3.15-3.111 (m, 1H);2.45 (s, 3H); 2.40 (s, 3H); 2.32 (s, 3H); 1.91-1.78 (m, 4H); 0.83-0.79(m, 6H) ppm.

Example 14 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(2,4-difluorophenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 2,4-difluorophenyl boronic acidproduces the title compound in 76% yield. MS, ES+=427.2 (M+1); ¹H-NMR(DMSO-d6)=8.370-8.310 (m, 1H); 7.586-7.540 (m, 1H); 7.36-7.32 (m, 1H);7.054 (s, 1H); 3.14-3.13 (m, 1H); 2.492 (s, 3H); 2.391 (s, 3H); 2.345(s, 3H); 1.906-1.797 (m, 4H); 0.826-0.788 (m, 6H) ppm.

Example 15 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(o-tolyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, o-tolyl boronic acid producesthe title compound in 87% yield where the crude mixture is purified bysilica gel chromatography using 2% methanol in dichloromethane as asolvent system. MS, ES+=405.2 (M+1); ¹H-NMR (DMSO-d6)=7.857-7.838 (d,1H); 7.429-7.419 (d, 2H); 7.393-7.352 (m, 1H); 7.049 (s, 1H);3.145-3.114 (m, 1H); 2.647 (s, 3H); 2.502 (s, 3H); 2.406 (s, 3H); 2.337(s, 3H); 1.907-1.782 (m, 4H); 0.827-0.791 (m, 6H) ppm.

Example 16 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(3,4-difluorophenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 3,4-difluorophenyl boronic acidproduces the title compound in 74% yield where the crude mixture ispurified by chromatography using 2% methanol in dichloromethane as asolvent system. MS, ES+=427.2 (M+1); ¹H-NMR (DMSO-d6)=8.07-8.02 (m, 1H);7.849 (s, 1H); 7.66-7.59 (m, 1H); 7.062 (s, 1H); 3.12-3.11 (m, 1H);2.498 (s, 3H); 2.392 (s, 3H); 2.319 (s, 3H) 1.905-1.779 (m, 4H);0.826-0.790 (m, 6H) ppm.

Example 17 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(4-fluoro-2-methylphenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 8, 4-fluoro-2-methylphenyl boronicacid produces the title compound 0.040 g (37% yield). MS, ES+=423.2(M+1); ¹H-NMR (DMSO-d6)=7.918-7.882 (m, 1H); 7.323-7.241 (d, 1H);7.234-7.192 (m, 1H); 7.049 (s, 1H); 3.142-3.111 (m, 1H); 2.650 (s, 3H);2.499 (s, 3H); 2.401 (s, 3H); 2.330 (s, 3H); 1.905-1.779 (m, 4H);0.969-0.788 (m, 6H) ppm.

Example 18 Preparation of8-(1-ethyl-propyl)-3-[4-methyl-2-(4-trifluoromethoxyphenyl)-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a microwave pressure tube is added 0.100 g (0.254 mmol) of8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine,0.157 g (0.762 mmol) of 4-(trifluoromethoxy)benzene boronic acid, 0.147g (0.127 mmol) of Pd(PPh3)4, 0.381 mL (0.762 mmol) of 2 M aqueous sodiumcarbonate, and 2 mL Ethanol. The reaction mixture is heated in themicrowave at 160° C. for up to 1 hour. The reaction mixture ispartitioned between 50 mL of ethyl acetate and 50 mL of water. Thelayers are separated and the aqueous is extracted 3×50 mL of ethylacetate, dried (MgSO4), and concentrated under vacuum. The crude mixtureis purified by chromatography using 2% methanol in dichloromethane as asolvent system. The product containing fractions are combined to obtain0.085 g of the product, 70% yield. MS, ES+=475.2 (M+1); ¹H-NMR(DMSO-d6)=8.134-8.112 (d, 2H); 7.553-7.532 (d, 2H); 7.059 (s, 1H);3.142-3.113 (m, 1H); 2.500 (s, 3H); 2.399 (s, 3H); 2.330 (s, 3H);1.907-1.782 (m, 4H); 0.827-0.791 (m, 6H) ppm.

Example 19 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

A. 4,4,5,5-Tetramethyl-2-(4-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane

To a 250 mL round bottom flask is added 3-bromo-4-methyl-thiophene (5.00g, 28.24 mmol), bis(pinacolato)diboron (7.89 g, 31.06 mmol) and KOAc(8.32 g, 84.72 mmol) in DMSO (85 mL). The mixture is degassed bybubbling N₂ for 5 min, PdCl₂(dppf)₂.CH₂Cl₂ (1.15 g, 1.42 mmol) is addedand the reaction mixture is heated to and stirred at 85° C. overnight.The reaction is cooled to rt, and diluted with EtOAc (400 mL), washedwith H₂O (3×300 μL); dried with MgSO₄, filtered and concentrated.Purification of the crude material by chromatography to give the titlecompound (3.69 g, 16.5 mmol, 58%). ES-MS (m/z): calcd for C₁₁H₁₇BO₂S(M⁺): 224.1. found: 224.9.

B. 4-Methyl 3-thiophene boronic acid

A solution of4,4,5,5-tetramethyl-2-(4-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane(3.69 g, 16.47 mmol) in acetone (30 mL) is treated with H₂O (30 mL),followed by NaIO₄ (7.05 g, 32.95 mmol). The resulting mixture is stirredat rt overnight. The organic solvent is removed in vacuo. The residue isdiluted with H₂O (50 mL), extracted with EtOAc ((2×100 mL). The organicextracts are combined, dried with Na₂SO₄, filtered and concentrated.Purification of the crude material by chromatography gives the titlecompound (0.82 g, 5.78 mmol, 35%). ¹H NMR (CDCl₃): δ 1.33 (s, 3H),2.64-2.66 (m, 2H), 7.00-7.02 (m, 1H), 8.27 (d, J=3.0 Hz, 1H). ES-MS(m/z): calcd for C₅H₇BO₂S (M−H)⁻: 141.0. found: 141.1.

C.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(4-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

To a 100 mL round bottom flask containing 4-methyl 3-thiophene boronicacid (0.27 g, 1.91 mmol), and8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.65 g,1.91 mmol) in 20 mL of a stock solution (DME:H₂O:EtOH=7:3:2) is added 2M Na₂CO₃ (1.9 mL). The resulting mixture is degassed by bubbling N₂ for5 min. Then Pd(PPh₃)₄ (0.11 g, 0.096 mmol) is added. The reactionmixture is refluxed overnight. The reaction is diluted with H₂O (20 mL);extracted with EtOAc (3×30 mL); dried (Na₂SO₄), filtered andpurification of the crude material by chromatography gives the titlecompound (0.52 g, 1.66 mmol, 87%). ¹H NMR (CDCl₃): δ 0.89 (t, J=7.5 Hz,6H), 1.75-1.90 (m, 4H), 2.13 (d, J=0.8 Hz, 3H), 2.44 (s, 3H), 2.49 (s,3H), 3.30-3.39 (m, 1H), 6.64 (s, 1H), 7.08-7.11 (m, 1H), 7.34 (d, J=3.1Hz, 1H). ES-MS (m/z): calcd for C₁₈H₂₃N₃S (M+H)⁺: 314.5. found: 314.2.

Example 20 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To mixture of8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (12.0 g,34.96 mmol) and PdCl₂(dppf) (1.28 g, 1.75 mmol) is added a 0.5 Msolution of 3-methyl-2-thienylzinc bromide in THF (100 mL, 50.0 mmol).The mixture is stirred at 65° C. overnight, diluted with EtOAc (500 mL),washed with 10% citric acid (500 mL), water (400 mL), brine (400 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO (10%-20% EtOAc/hexane gradient) furnish the title compound (8.83 g,28.17 mmol, 81%). ¹H NMR (CDCl₃), δ 0.92 (t, J=7.4 Hz, 6H), 1.78-1.95(m, 4H), 2.18 (s, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 3.33-3.43 (m, 1H),6.69 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 7.46 (d, J=4.9 Hz, 1H). LC/MS(m/z): calcd. for C₁₈H₂₃N₃S (M+H)⁺: 314.6. found: 314.2.

Example 21 Preparation of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine(8.83 g, 28.17 mmol) and CH₂Cl₂ (90 mL) is added NBS (5.26 g, 29.58mmol). The solution is stirred at ambient temperature for 2 hours. Thesolution is washed with water (3×75 mL), dried over MgSO4, filtered andconcentrated to furnish the title compound (10.5 g, 26.76 mmol, 95%). ¹HNMR (CDCl₃), δ 0.87 (t, J=7.3 Hz, 6H), 1.73-1.93 (m, 4H), 2.09 (s, 3H),2.44 (s, 3H), 2.51 (s, 3H), 3.26-3.36 (m, 1H), 6.68 (s, 1H), 6.98 (d,J=4.9 Hz, 1H) ppm. LC/MS (m/z): calcd. for C₁₈H₂₂BrN₃S (M+H)⁺: 392.6.found: 392.1, 394.1.

Example 22 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid methyl ester

A solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(1.00 g, 2.66 mmol) in CH₃OH (12 mL), DMSO (18 mL), Et₃N (2.0 mL) withPd(OAc)₂ (0.12 g, 0.538 mmol), dppf (0.937 g, 1.69 mmol) is reacted atCO atmosphere (100 psi) at 80° C. for 24 h. The reaction mixture isdiluted with EtOAc (200 mL), washed with 0.1 M HCl (2×50 mL), brine (50mL); dried with Na₂SO₄; filtered through silica gel and eluted withexcess EtOAc. Purification of the crude material by chromatography givesthe title compound (0.79 g, 2.12 mmol, 80%). ¹H NMR (CDCl₃): δ 0.89 (t,J=7.7 Hz, 6H), 1.75-1.93 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H), 2.53 (s,3H), 3.32-3.42 (m, 1H), 3.91 (s, 3H), 6.72 (s, 1H), 7.73 (s, 1H). ES-MS(m/z): calcd for C₂₀H₂₅N₃O₂S (M+H)⁺: 372.5. found: 372.2.

Example 23 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid methylamide

A.5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid

A solution of(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid methyl ester (0.78 g, 2.10 mmol) in CH₃OH (10 mL) is treated with5.0 M NaOH (2.1 mL, 10.5 mmol). The resulting reaction mixture isrefluxed for 4 h. Organic solvent is removed in vacuo; the aqueousresidue is acidified by the addition of 2.0 M HCl to pH 5˜6; it is thenextracted with EtOAc (3×50 mL); dried (Na₂SO₄); filtered andconcentration to give the title compound (0.74 g, 2.07 mmol, 98%). ¹HNMR (DMSO-d6): δ 0.79 (t, J=7.6 Hz, 6H), 1.75-1.86 (m, 4H), 2.06 (s,3H), 2.36 (s, 3H), 2.47 (s, 3H), 3.06-3.14 (m, 1H), 7.01 (s, 1H), 7.68(s, 1H), 13.1 (bs, 1H). ES-MS (m/z): calcd for C₁₉H₂₃N₃O₂S (M+H)⁺:358.5. found: 358.2.

B.5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid methylamide

5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid (0.17 g, 0.47 mmol) is reacted with 2.0 M oxalyl chloride in CH₂Cl₂(3.0 mL) at rt for 1 h. The excess reagent and solvent are removed invacuo. The residue is dissolved in CH₂Cl₂ (3 mL), cooled to 0° C. andtreated with 2.0 M methyl amine in THF (3 mL). The reaction is stirredat 0° C. for 10 min and rt for 30 min. It is diluted with EtOAc (50 mL),washed with H₂O (15 mL0, 0.1 M NaOH (2×30 mL); dried (Na₂SO₄); filteredand concentrated. Purification of the crude material by chromatographyto give the title compound (0.91 g, 0.25 mmol, 53%). ¹H NMR (CDCl₃): δ0.89 (t, J=7.2 Hz, 6H), 1.75-1.91 (m, 4H), 2.14 (s, 3H), 2.47 (s, 3H),2.52 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 3.28-3.36 (m, 1H), 5.90-6.01 (m,1H), 6.69 (s, 1H), 7.43 (s, 1H). ES-MS (m/z): calcd for C₂₀H₂₆N₄OS(M+H)⁺: 371.5. found: 371.2.

Example 24 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-imidazol-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo-[1,2-b]pyridazine(0.98 g, 2.51 mmol) and 1-methyl-1H-imidazole (0.2 mL), Pd(OAc)₂ (34 mg,0.15 mmol), PPh₃ (79 mg, 0.299 mmol), Cs₂CO₃ (1.95 g, 6.0 mmol) in DMF(50 mL) is stirred under N₂ at 130-140° C. overnight. The reactionmixture is cooled, diluted with EtOAc (300 mL), washed with H₂O (3×100mL); dried (Na₂SO₄); filtered and concentrated. Purification of theresulting crude material by chromatography yields the title compound(0.51 g, 1.29 mmol, 51%). ¹H NMR (CDCl₃): δ 0.89 (t, J=7.5 Hz, 6H),1.77-1.92 (m, 4H), 2.17 (s, 3H), 2.51 (s, 3H), 2.54 (s, 3H), 3.30-3.40(m, 1H), 3.81 (s, 3H), 6.69 (s, 1H), 7.02 (s, 1H), 7.24 (s, 1H), 7.52(s, 1H). ES-MS (m/z): calcd for C₂₂H₂₇N₅S (M+H)⁺: 394.6. found: 394.3.

Example 25 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.15 mL, 2.04 mmol)and THF (3 mL) is added a 1.34 M solution of n-Bu-Li in hexanes (1.60mL, 2.14 mmol) over 20 minutes, then stirred at −78° C. for 1.5 hours. A0.5 M solution of ZnCl₂ in THF (4.28 mL, 2.14 mmol) is added and thesolution warmed to ambient temperature.3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.019 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) is added andthe solution heated at 65° C. overnight diluted with CH₂Cl₂ (30 mL). Theorganic layer is washed with 10% citric acid (20 mL), water (20 mL),brine (20 mL), dried over MgSO₄, filtered and concentrated. The residueis purified by ISCO (20%-60% EtOAc/hexane gradient). The residue isdissolved in Et₂O, treated with Darco®-60 for 15 minutes, dried withNa₂SO₄, and filtered to furnish the title compound (0.24 g, 0.61 mmol,60%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.4 Hz, 6H), 1.75-1.93 (m, 4H), 2.20(s, 3H), 2.50 (s, 3H), 2.51 (s, 3H), 3.28-3.37 (m, 1H), 4.14 (s, 3H),6.69 (s, 1H), 7.45 (s, 1H), 7.87 (s, 1H). LC/MS (m/z): calcd. forC₂₁H₂₆N₆S (M+H)⁺: 395.6. found: 395.2.

Example 26 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carbonitrile

A solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.28 mmol), DMF (5 mL), and Zn(CN)₂ (0.090 g, 0.76 mmol) isdegassed with nitrogen for 15 minutes. Pd(PPh₃)₄ (0.74 g, 0.064 mmol)and the solution heated at 100° C. overnight. The solution is dilutedwith EtOAc (50 mL), washed with 2 M NH₄OH (2×30 mL), brine (30 mL),dried over MgSO₄, filtered and concentrated. Purified by ISCO columnchromatography (15%-20% EtOAc/hexane gradient) furnish the titlecompound (0.39 g, 1.15 mmol, 91%). ¹H NMR (CDCl₃), δ 0.87 (t, J=7.5 Hz,6H), 1.74-1.91 (m, 4H), 2.15 (s, 3H), 2.46 (s, 3H), 2.51 (s, 3H),3.26-3.34 (m, 1H), 6.72 (s, 1H), 7.53 (s, 1H). LC/MS (m/z): calcd. forC₁₉H₂₂N₄S (M+H)⁺: 339.6. found: 339.2.

Example 27 Preparation of(2-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyrrol-1-yl)-dimethyl-amine

To a 0° C. solution 1-(dimethylamino)-pyrrole (0.24 mL, 2.04 mmol) andTHF (4 mL) is added 1.24 M n-BuLi (1.73 mL, 2.14 mmol). The solution iswarmed to ambient temperature and stirred for two hours. 0.5 M ZnCl₂(4.28 mL, 2.14 mmol) is added and the solution is stirred for one hour.3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) is added andthe solution is heated at 65° C. overnight. The solution is diluted withEtOAc (30 mL), washed with sat. NH₄Cl (30 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO flashchromatography (15%-20% EtOAc gradient) furnish the title compound (0.41g, 0.97 mmol, 95%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91(m, 4H), 2.11 (s, 3H), 2.51 (s, 6H), 2.83 (s, 6H), 3.29-3.39 (m, 1H),6.18-6.21 (m, 1H), 6.35 (dd, J=4.0, 1.8 Hz, 1H), 6.65 (s, 1H), 6.98 (dd,J=4.0, 1.8 Hz, 1H), 7.25 (s, 1H). LC/MS (m/z): calcd. for C₂₄H₃₁N₅S(M+H)⁺: 422.2. found: 422.4.

Example 28 and 29 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(2-methyl-2,5-dihydro-1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazineand8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2b]pyridazine

A.8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a solution of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carbonitrile(0.25 g, 0.74 mmol) and DMF (2.5 mL) is added Et₃N.HCl (0.31 g, 2.22mmol) and NaN₃ (0.14 g, 2.20 mmol). The solution is heated at 100° C.overnight. The solution is diluted with water (20 mL) and extracted withEtOAc (3×15 mL), the combined organic layers are washed with 0.1 M HCl(20 mL), water (20 mL), brine (20 mL), dried over MgSO₄, filtered andconcentrated. The residue is recrystallized from acetonitrile furnishthe title compound (0.14 g, 0.37 mmol, 50%). ¹H NMR (CDCl₃), δ 0.81 (t,J=7.5 Hz, 6H), 1.66-1.87 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.53 (s,3H), 3.26-3.35 (m, 1H), 6.83 (s, 1H), 7.84 (s, 1H). LC/MS (m/z): calcd.for C₁₉H₂₃N₇S (M+H)⁺: 382.6. found: 382.2.

B.8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(2-methyl-2,5-dihydro-1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazineand8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2b]pyridazine

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine(0.14 g, 0.35 mmol) and THF (3 mL) is added Et₃N (0.1 mL, 0.71 mmol) andMeI (0.024 mL, 0.39 mmol). The solution is stirred overnight, dilutedwith EtOAc (20 mL), washed with water (15 mL), 0.1 M HCl (15 mL), brine(15 mL), dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO column chromatography (20%-40% EtOAc/hexane gradient)furnish Ex. 28 (0.71 g, 0.18 mmol, 51%), and Ex. 29 (0.031 g, 0.078mmol, 22%).

Ex. 28: ¹H NMR (CDCl₃), δ 0.88 (t, J=7.4 Hz, 6H), 1.75-1.92 (m, 4H),2.18 (s, 3H), 2.50 (s, 3H), 2.51 (s, 3H), 3.28-3.38 (m, 1H), 4.38 (s,3H), 6.68 (s, 1H), 7.71 (s, 1H). LC/MS (m/z): calcd. for C₂₀H₂₅N₇S(M+H)⁺: 396.6. found: 396.3.

Ex. 29: ¹H NMR (CDCl₃), δ 0.89 (t, J=7.4 Hz, 6H), 1.73-1.94 (m, 4H),2.23 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.28-3.37 (m, 1H), 4.30 (s,3H), 6.62 (s, 1H), 7.63 (s, 1H). LC/MS (m/z): calcd. for C₂₀H₂₅N₇S(M+H)⁺: 396.6. found: 396.3.

Example 30 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

A. 3-(5-Boronicacid-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(1.20 g, 3.06 mmol) and THF (10 mL) is added 1.30 M n-Bu-Li (2.47 mL,3.21 mmol) drop wise. The solution is stirred at −78° C. for one hour.B(OMe)₃ (0.38 mL, 3.65 mmol) is added and the solution is warmed toambient temperature and stirred for 2 hours. 1 M HCl is added and thesolution stirred for 10 minutes extracted with CH₂Cl₂ (2×30 mL), driedover MgSO₄, filtered and concentrated to furnish the title compound(0.47 g, 1.32 mmol, 43%). ¹H NMR (CDCl₃), δ 0.92 (t, J=7.5 Hz, 6H),1.71-1.98 (m, 4H), 2.02 (s, 3H), 2.64 (s, 3H), 2.69 (s, 3H), 3.64-3.83(m, 1H), 7.06 (d, J=5.3 Hz, 1H), 7.54 (d, J=5.3 Hz, 1H), 7.20 (s, 1H).LC/MS (m/z): calcd. for C₁₈H₂₄BN₃O₂S (M+H)⁺: 358.4. found: 358.2.

B.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

A solution of 3-(5-boronicacid-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.70 mmol), 4-bromopyridine hydrochloride (0.16 g, 0.84 mmol),and 2 M Na₂CO₃ (0.87 mL, 1.75 mmol) and n-PrOH (2.5 mL) is degassed withnitrogen for 10 minutes. Pd(PPh₃)₄ (0.040 g, 0.035 mmol) is added andthe solution heated at 85° C. overnight. The solution is diluted withCH₂Cl₂ (40 mL), washed with 10% Na₂CO₃ (30 mL), water (30 mL), brine (30mL), dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO column chromatography (20%-40% EtOAc/hexane gradient)furnish the title compound (0.16 g, 0.41 mmol, 59%). ¹H NMR (CDCl₃), δ0.88 (t, J=7.5 Hz, 6H), 1.74-1.93 (m, 4H), 2.17 (s, 3H), 2.49 (s, 3H),2.52 (s, 3H), 3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.43 (s, 1H), 7.52 (d,J=5.5 Hz, 2H), 8.62 (d, J=5.5 Hz, 2H). LC/MS (m/z): calcd. for C₂₃H₂₆N₄S(M+H)⁺: 391.2 found: 391.2.

Example 31 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-3-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol), and THF (5 mL) is added 1.34 M n-Bu-Li (1.0 mL,1.34 mmol). The solution is stirred for at −78° C. for 30 minutes and0.5 M ZnCl₂ in THF (2.7 mL, 1.34 mmol) is added and the solution warmedto ambient temperature. After 30 minutes 3-bromopyridine (0.15 mL, 1.53mmol) and PdCl₂(dppf) (0.047 g, 0.064 mmol) is added and the solutionheated at 65° C. overnight. The solution is diluted with CH₂Cl₂ (40 mL),washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL) driedover MgSO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (20%-40% EtOAc/hexane gradient) concentrated andre-dissolved in Et₂O. The solution is treated with Darco®-60 for 15minutes, dried over Na₂SO₄, and filtered thru Celite® furnish the titlecompound (0.26 g, 0.67 mmol, 52%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz,6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H),3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.26-7.32 (m, 2H), 7.86 (dt, J=7.9, 1.8Hz, 1H), 850 (d, J=3.2 Hz, 1H), 8.89 (s, 1H). LC/MS (m/z): calcd. forC₂₃H₂₆N₄S (M+H)⁺: 391.6. found: 391.2.

Example 32 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To a mixture of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol) and PdCl₂(dppf) (0.047 g, 0.064 mmol) is added a 0.5M solution of 2-pyridylzinc bromide in THF (5.1 mL, 2.55 mmol). Themixture is stirred at 65° C. overnight, diluted with EtOAc (50 mL),washed with 10% citric acid (50 mL), water (40 mL), brine (40 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (20%-40% EtOAc/hexane gradient) furnish the titlecompound (0.45 g, 1.15 mmol, 89%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz,6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.52 (s, 6H), 3.30-3.39 (m, 1H),6.67 (s, 1H), 7.12-7.16 (m, 1H), 7.53 (s, 1H), 7.63-7.71 (m, 2H), 8.57(dt, J=1.3, 4.8 Hz, 1H). LC/MS (m/z): calcd. for C₂₃H₂₆N₄S (M+H)⁺:391.6. found: 391.2.

Example 33 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazinehydrochloride

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine(0.15 g, 38 mmol) and MeOH (2 mL) is added AcCl (0.028 mL, 0.39 mmol).After one hour the solution is concentrated and the residuerecrystallized from EtOAc/hexane furnish the title compound (0.11 g,0.26 mmol, 69%). ¹H NMR (CDCl₃), δ 0.97 (t, J=7.4 Hz, 6H), 1.75-2.03 (m,4H), 2.17 (s, 3H), 2.66 (s, 3H), 2.77 (s, 3H), 3.86-3.98 (m, 1H), 7.17(s, 1H), 7.21-7.30 (m, 2H), 7.62 (bs, 1H), 7.67-7.7.82 (m, 2H), 8.60 (d,J=4.8 Hz, 1H). LC/MS (m/z): calcd. for C₂₃H₂₆ClN₅S (M+H)⁺: 428.1. found:391.2.

Example 34 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(2-methyl-2H-pyrazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25, 1-methylpyrazole (0.17 g, 2.04mmol), 1.56 M n-Bu-Li (1.34 mL, 2.09 mmol), ZnCl₂ (4.3 mL, 2.14 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.35 g, 0.89 mmol, 88%). ¹H NMR (CDCl₃), δ 0.88 (t,J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.52 (s,3H), 3.28-3.38 (m, 1H), 4.05 (s, 3H), 6.42 (d, J=1.8 Hz, 1H), 6.68 (s,1H), 7.08 (s, 1H), 7.46 (d, J=1.8 Hz, 1H). LC/MS (m/z): calcd. forC₂₂H₂₇N₅S (M+H)⁺: 394.7. found: 394.2.

Example 35 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-thiazol-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 31, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol), 1.34 M n-Bu-Li (0.8 mL, 1.07 mmol), 0.5 M ZnCl₂ inTHF (2.14 mL, 1.07 mmol), 4-bromo-thiazole (0.20 mL, 1.22 mmol) andPdCl₂(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.16 g,0.40 mmol, 40%). ¹H NMR (CDCl₃), δ 0.92 (t, J=7.4 Hz, 6H), 1.70-1.96 (m,4H), 2.17 (s, 3H), 2.64 (s, 3H), 2.66 (s, 3H), 3.38-3.48 (m, 1H), 7.16(d, J=1.8 Hz, 1H), 7.44 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.8Hz, 1H). LC/MS (m/z): calcd. for C₂₁H₂₄N₄S₂ (M+H)⁺: 397.7. found: 397.2.

Example 36 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.60 g, 1.53 mmol) and PdCl₂(dppf) (0.056 g, 0.076 mmol) and 0.5 Msolution of 6-methyl-2-pyridylzinc bromide in THF (6.0 mL, 3.06 mmol)furnish the title compound (0.29 g, 0.72 mmol, 47%). ¹H NMR (CDCl₃), δ0.89 (t, J=7.5 Hz, 6H), 1.73-1.93 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H),2.52 (s, 3H), 2.58 (s, 3H), 3.31-3.40 (m, 1H), 6.67 (s, 1H), 7.00 (d,J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 8.56 (t, J=7.7 Hz,1H). LC/MS (m/z): calcd. for C₂₄H₂₈N₄ (M+H)⁺: 405.7. found: 405.2.

Example 37 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-phenyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol) and PdCl₂(dppf) (0.05 g, 0.069 mmol) and 0.5 Msolution of phenylzinc iodide in THF (5.5 mL, 2.76 mmol) furnish thetitle compound (0.25 g, 0.64 mmol, 50%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.17 (s, 3H), 2.52 (s, 3H), 2.53 (s,3H), 3.31-3.41 (m, 1H), 6.68 (s, 1H), 7.26 (s, 1H), 7.27-30 (m, 1H),7.35-7.41 (m, 2H), 7.61-7.66 (m, 2H). LC/MS (m/z): calcd. for C₂₄H₂₇N₃S(M+H)⁺: 390.3. found: 390.3.

Example 38 Preparation of8-(1-ethyl-propyl)-3-[5-(3-fluoro-phenyl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol) and PdCl₂(dppf) (0.047 g, 0.063 mmol) and 0.5 Msolution of 3-fluorophenylzinc iodide in THF (5.1 mL, 2.55 mmol) furnishthe title compound (0.24 g, 0.59 mmol, 46%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.17 (s, 3H), 2.51 (s, 3H), 2.53 (s,3H), 3.31-3.39 (m, 1H), 6.69 (s, 1H), 6.94-7.01 (m, 1H), 7.26 (s, 1H),7.30-7.42 (m, 3H). LC/MS (m/z): calcd. for C₂₄H₂₆FN₃S (M+H)⁺: 408.7.found: 408.2.

Example 39 Preparation of8-(1-ethyl-propyl)-3-[5-(4-fluoro-phenyl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A slurry of 0.05 g/mL of Reike® Zn in THF (0.26 g, 4.01 mmol) and1-bromo-4-fluoro-benzene (0.29 mL, 2.68 mmol) is heated at a refluxovernight. The solution is filtered under nitrogen.3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.35 g, 0.89 mmol) and PdCl₂(dppf) (0.033 g, 0.045 mmol) are added, andthe solution is heated at a reflux overnight diluted with EtOAc (30 mL),washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (10%-15% EtOAc/hexane gradient) furnish the titlecompound (0.091 g, 0.22 mmol, 25%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz,6H), 1.74-1.92 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H),3.30-3.38 (m, 1H), 6.68 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.18 (s, 1H),7.59 (dd, J=8.5, 5.3 Hz, 2H). LC/MS (m/z): calcd. for C₂₄H₂₆FN₃S (M+H)⁺:408.7. found: 408.3.

Example 40 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-ethyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 31, 2-bromo-6-ethyl pyridine (0.26g, 1.41 mmol), 1.56 M n-Bu-Li (0.94 mL, 1.47 mmol), 0.5 M ZnCl₂ in THF(3.0 mL, 1.53 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol) and PdCl₂(dppf) (0.047 g, 0.064 mmol) produce thetitle compound (0.15 g, 0.36 mmol, 28%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.5 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H), 1.75-1.94 (m, 4H), 2.16 (s, 3H),2.51 (s, 3H), 2.52 (s, 3H), 2.85 (q, J=16.2, 7.5 Hz, 2H), 3.31-3.41 (m,1H), 6.67 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.53(s, 1H), 8.59 (t, J=7.8 Hz, 1H). LC/MS (m/z): calcd. for C₂₅H₃₀N₄S(M+H)⁺: 419.3. found: 419.3.

Example 41 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazinehydrochloride

Using a procedure similar to Example 33,8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine(0.55 g, 1.36 mmol), MeOH (6 mL) and AcCl (0.098 mL, 1.36 mmol) furnishthe title compound (0.11 g, 0.25 mmol, 42%). ¹H NMR (CDCl₃), δ 0.96 (t,J=7.2 Hz, 6H), 1.74-1.89 (m, 2H), 1.89-2.02 (m, 2H), 2.22 (s, 3H), 2.68(s, 3H), 2.78 (s, 3H), 3.08 (s, 3H), 3.88-3.98 (m, 1H), 7.23 (s, 1H),7.40 (d, J=6.9 Hz, 1H), 7.71 (d, J=4.8 Hz, 1H), 8.06 (s, 1H), 8.82 (s,1H). LC/MS (m/z): calcd. for C₂₄H₂₉ClN₄S (M+H)⁺: 441.3. found: 405.2.

Example 42 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-thiazol-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.46 g, 1.17 mmol), 0.5 M 2-thiazolylzinc bromide in THF (4.7 mL, 2.35mmol) and PdCl₂(dppf) (0.043 g, 0.059 mmol) furnish the title compound(0.32 g, 0.81 mmol, 70%). ¹H NMR (CDCl₃), δ 0.90 (t, J=7.5 Hz, 6H),1.76-1.94 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.31-3.40(m, 1H), 7.70 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.47 (s, 1H), 7.78 (d,J=3.6 Hz, 1H). LC/MS (m/z): calcd. for C₂₁H₂₄N₄S₂ (M+H)⁺: 397.7. found:397.1.

Example 43 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyrazin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 31,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) (example Rupp-2), 2-chloropyrazine (0.11 mL, 1.22mmol), 1.42 M n-Bu-Li (1.52 mL, 1.07 mmol), 0.5 M ZnCl₂ in THF (2.14 mL,1.07 mmol), and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish the titlecompound (0.19 g, 0.49 mmol, 48%). ¹H NMR (CDCl₃), δ 0.90 (t, J=7.5 Hz,6H), 1.75-1.94 (m, 4H), 2.20 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H),3.31-3.40 (m, 1H), 6.69 (s, 1H), 7.63 (s, 1H), 8.40 (d, J=2.6 Hz, 1H),8.51 (t, J=1.9 Hz, 1H), 8.96 (d, J=0.9 Hz, 1H). LC/MS (m/z): calcd. forC₂₂H₂₅N₅S (M+H)⁺: 392.3. found: 392.2.

Example 44 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-[2,2′]bithiophenyl-5-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol), 0.5 M 2-thiophenlyzinc bromide in THF (3.0 mL, 1.53mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) furnish the title compound(0.25 g, 0.63 mmol, 83%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H),1.75-1.93 (m, 4H), 2.14 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 3.30-3.39(m, 1H), 6.68 (s, 1H), 7.02 (dd, J=5.0, 3.6 Hz, 1H), 7.11 (s, 1H), 7.19(d, J=3.6 Hz, 1H), 7.19 (dd, J=5.0, 1.0 Hz, 1H). LC/MS (m/z): calcd. forC₂₂H₂₅N₃S₂ (M+H)⁺: 396.7. found: 396.2.

Example 45 Preparation of3-(5-butyl-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25 from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 0.1.02 mmol), 1.34 M n-Bu-Li (1.60 mL, 2.14 mmol), 0.5 M ZnCl₂(4.3 mL, 2.14 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnishes thetitle compound (0.25 g, 0.69 mmol, 68%). ¹H NMR (CDCl₃), δ 0.88 (t,J=7.5 Hz, 6H), 0.97 (t, J=7.5 Hz, 3H), 1.40-1.51 (m, 2H), 1.67-1.92 (m,6H), 2.07 (s, 3H), 2.46 (s, 3H), 2.51 (s, 3H), 2.83 (t, J=8.0 Hz, 2H),3.30-3.38 (m, 1H), 6.64 (s, 1H), 6.70 (s, 1H) LC/MS (m/z): calcd. forC₂₂H₃₁N₃S (M+H)⁺: 370.3. found: 370.2.

Example 46 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-pyrazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 31,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol), 1.42 M n-Bu-Li (0.75 mL, 1.07 mmol), 0.5 M ZnCl₂ inTHF (2.14 mL, 1.07 mmol), 3-bromo-1-methyl-1H-pyrazole (Pavlik, J.;Kurzweil, E.; J. Org. Chem., 1991, 56, 22, 6313) (0.20 g, 1.22 mmol) andPdCl₂(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.041 g,0.10 mmol, 10%). ¹H NMR (CDCl₃) δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.94 (m,4H), 2.15 (s, 3H), 2.51 (s, 3H), 2.52 (s, 3H), 3.31-3.41 (m, 1H), 3.95(s, 3H), 6.47 (d, J=2.2 Hz, 1H), 6.67 (s, 1H), 7.25 (s, 1H), 7.36 (d,J=2.2 Hz, 1H). LC/MS (m/z): calcd. for C₂₂H₂₇N₅S (M+H)⁺: 394.3. found:394.2.

Example 47 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-imidazo[1,2-b]pyridazine

82 mg of 1-Methyl-1,2,4-triazole (0.99 mmol) is dissolved in 2 ml of dryTHF and cooled to −78° C. and 0.4 ml of n-butyllithium 2.5 M in hexane(0.99 mmol) is added. The reaction mixture is stirred at −78 C to roomtemperature for 10 min and cooled to −78° C. again. 1.98 ml of 0.5 Mzinc chloride 0.5 M solution in THF (0.99 mmol) is added and stirred at−78 C to room temperature for 15 min. 265 mg of3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.66 mmol) and 27 mg of PdCl2(dppf) (0.033 mmol) are added and the vialis capped with a Teflon cap and heated at 80° C. for 2 days. Thereaction is cooled to room temperature and quenched with sat. NH4Cl andextracted with CH2Cl2. The separated CH2Cl2 layer is dried over Na2SO4and evaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:2:1) to give 57mg of the title product. Yield 22%. mass spectrum (m/e): 396 (M+1).¹H-NMR (CDCl₃): δ 7.96 (s, 1H), 6.77 (s, 1H), 4.45 (s, 3H), 3.36 (m,1H), 2.55 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 1.88 (m, 4H), 0.92 (t,J=7.3 Hz, 6H).

Example 48 Preparation of3-[4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

82 mg of 1-methyl-1,2,4-triazole (0.99 mmol) is dissolved in 2 ml of dryTHF and cooled to −78° C. and 0.4 ml of n-butyllithium 2.5 M in hexane(0.99 mmol) is added. The reaction mixture is stirred at −78° C. to roomtemperature for 10 min and cooled to −78° C. again. 1.98 ml of 0.5 Mzinc chloride 0.5 M solution in THF (0.99 mmol) is added and stirred at−78° C. to room temperature for 15 min. 152 mg of3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.33 mmol) and 27 mg of PdCl2(dppf) (0.033 mmol) are added and the vialis capped with a Teflon cap and heated at 80° C. for 2 days. Thereaction is cooled to room temperature and quenched with sat. NH4Cl1 andextracted with CH2Cl2. The separated CH2Cl2 layer is dried over Na2SO4and evaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give 88 mgof the title product. Yield 54%. mass spectrum (m/e): 461 (M+1). ¹H-NMR(CDCl₃): 7.98 (s, 1H), 6.77 (s, 1H), 4.44 (s, 3H), 3.35 (m, 1H), 2.59(s, 3H), 2.55 (s, 3H), 1.88 (m, 4H), 0.92 (t, J=7.5 Hz, 6H).

Example 49 Preparation of3-[4-chloro-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

175 mg of3-[4-Bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.38 mmol) and 56 mg of copper chloride (0.57 mmol) are placed into 4ml vial with 3.0 ml of dry DMF and the vial is capped with a Teflon cap.The vial is heated at 130° C. overnight. The reaction mixture is appliedonto a silica-gel chromatography column (Hexane:AcOEt=3:1 andhexane:AcOEt=8:1) to give 91 mg of crude product. The pure product isrecrystallized from Et2O/Hexane. 73 mg (46%). mass spectrum (m/e): 416(M+1). ¹H-NMR (CDCl₃): 7.98 (s, 1H), 6.80 (s, 1H), 4.44 (s, 3H), 3.35(m, 1H), 2.59 (s, 3H), 1.88 (m, 4H), 0.92 (t, J=7.5 Hz, 6H).

Example 50 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-oxazol-5-yl)-imidazo[1,2-b]pyridazine

686 mg of8-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.0mmol), 830 mg of 4-methyl-oxazole. (10 mmol), 105 mg oftriphenylphosphine (0.4 mmol) and 1.30 g of cesium carbonate (4.0 mmol)are placed into tube with 10 ml of dry DMF. N2 gas is bubbled in for 20min and 92 mg of Pd2 dba3 (0.1 mmol) is added. The tube is sealed andheated at 130° C. overnight. After being cooled to room temperature,water and CHCl2 are added to the mixture. The CHCl2 layer is separated,washed with sat. NaCl, dried over Na2SO4 and evaporated. The crudeproduct is applied onto a silica-gel chromatography column(Hexane:AcOEt=5:1) to give 234 mg of the title product. Yield 39%. massspectrum (m/e): 299 (M+1). ¹H-NMR (CDCl3): 8.06 (s, 1H), 6.75 (s, 1H),3.34 (m, 1H), 2.56 (s, 3H), 2.50 (s, 3H), 2.29 (s, 3H), 1.86 (m, 4H),0.90 (t, J=7.4 Hz, 6H).

Example 51 Preparation ofN-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-oxazol-2-yl}-dimethylamine

A.3-(2-Bromo-4-methyl-oxazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

230 mg of8-(1-Ethyl-propyl)-2,6-dimethyl-3-(4-methyl-oxazol-5-yl)-imidazo[1,2-b]pyridazine(0.77 mmol) is dissolved in 20 ml of CH2Cl2 and 178 mg of NBS (1.0 mmol)is added. The reaction mixture is stirred at room temperature overnight.The reaction mixture is washed with sat. Na2S2O3, sat. NaCl, dried overNa2SO4 and evaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1) to give 36 mg of the titlecompound. Yield 12%. mass spectrum (m/e): 378 (M+1). ¹H-NMR (CDCl3):6.82 (s, 1H), 3.39 (m, 1H), 2.58 (s, 3H), 2.53 (s, 3H), 2.26 (s, 3H),1.85 (m, 1H), 0.89 (t, J=7.4 Hz, 6H).

B.N-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-oxazol-2-yl}-dimethylamine

32 mg of3-(2-Bromo-4-methyl-oxazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.08 mmol) and 78 mg of cesium carbonate (0.24 mmol) are placed intovial with 3 ml of dimethylamine 2.0 M in THF. The vial is capped with aTeflon cap and heated at 110° C. for 3 days. The reaction mixture iscooled to room temperature, concentrated, and applied onto a silica-gelchromatography column (Hexane:AcOEt:2M NH3 in MeOH=10:2:1) to give 24 mgof the title product. Yield 89%. mass spectrum (m/e): 342 (M+1). ¹H-NMR(CDCl3): 6.71 (s, 1H), 3.34 (m, 1H), 3.13 (s, 6H), 2.56 (s, 3H), 2.49(s, 3H), 2.14 (s, 3H), 1.84 (m, 4H), 0.89 (t, J=7.5 Hz, 6H).

Example 52 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[(4-methyl-2-ethylamino)-thiazol-5-yl]-imidazo[1,2-b]pyridazine

The title compound is prepared essentially as described in Example 51B.employing 2.0 ml of ethylamine 2.0 M in THF and 182 g of cesiumcarbonate (0.56 mmol), 78%. mass spectrum (m/e): 358 (M+1); ¹H-NMR(CDCl3): 6.69 (s, 1H), 5.23 (br, 1H), 3.38 (m, 3H), 2.56 (s, 3H), 2.46(s, 3H), 2.17 (s, 3H), 1.85 (m, 4H), 1.35 (t, 3H, J=7.2 Hz), 0.90 (t,6H, J=7.2 Hz).

Example 53 Preparation of3-[5-(2,4-dimethyl-thiazol-5-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. mixture of 2,4-dimethylthiazole (0.23 g, 2.04 mmol) and THF(3 mL) is added 1.6 M t-Bu-Li in hexane (1.30 mL, 2.09 mmol). Themixture is stirred at −78° C. for 15 minutes. 0.5 M ZnCl₂ in THF (4.3mL, 2.14 mmol) is added and the solution warmed to ambient temperature.3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) is added andmixture is stirred at 65° C. overnight, diluted with EtOAc (20 mL),washed with 10% citric acid (15 mL), water (15 mL), brine (15 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by silicagel chromatography (0%-15% EtOAc/hexane gradient) furnish the titlecompound (0.21 g, 0.49 mmol, 49%). ¹H NMR (CDCl₃), δ 0.87 (t, J=7.5 Hz,6H), 1.73-1.91 (m, 4H), 2.14 (s, 3H), 2.49 (s, 3H), 2.52 (s, 3H), 2.57(s, 3H), 2.66 (s, 3H), 3.28-3.38 (m, 1H), 6.68 (s, 1H), 7.00 (s, 1H).LC/MS (m/z): calcd. for C₂₃H₂₈N₄S₂ (M+H)⁺: 425.3. found: 425.2.

Example 54 Preparation of3-[5-(4,5-dimethyl-thiazol-2-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25, from 4,5-dimethylthiazole (0.22mL, 2.04 mmol), 1.56 M n-Bu-Li (1.34 mL, 2.09 mmol), ZnCl₂ (4.3 mL, 2.14mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.27 g, 0.64 mmol, 63%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.13 (s, 3H), 2.36 (s, 3H), 2.38 (s,3H), 2.49 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.67 (s, 1H), 7.32(s, 1H). LC/MS (m/z): calcd. for C₂₃H₂₈N₄S₂ (M+H)⁺: 425.3. found: 425.2.

Example 55 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(2-methyl-pyridin-4-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 31, from 4-bromo-2-methylpyridine(Fukaya et. el. Chem. Pharm. Bull., 1990, 38, 2446) (0.21 g, 1.22 mmol),1.56 M n-Bu-Li (0.69 mL, 1.07 mmol), 0.5 M ZnCl₂ in THF (2.2 mL, 1.12mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.058 g, 0.14 mmol, 14%). ¹H NMR (CDCl₃), δ 0.87 (t,J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.16 (s, 3H), 2.48 (s, 3H), 2.51 (s,3H), 2.58 (s, 3H), 3.27-3.37 (m, 1H), 6.68 (s, 1H), 7.29 (d, J=5.3 Hz,1H), 7.35 (s, 1H), 7.41 (s, 1H), 8.46 (t, J=5.3 Hz, 1H). LC/MS (m/z):calcd. for C₂₄H₂₈N₄S (M+H)⁺: 405.3. found: 405.2.

Example 56 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 31, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol), 1.42 M n-Bu-Li (0.75 mL, 1.07 mmol), 0.5 M ZnCl₂ inTHF (2.14 mL, 1.07 mmol), 4-bromo-1-methyl-1H-pyrazole (0.25 g, 1.53mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnishes the title compound(0.092 g, 0.23 mmol, 23%). ¹H NMR (CDCl₃) δ 0.88 (t, J=7.4 Hz, 6H),1.73-1.92 (m, 4H), 2.12 (s, 3H), 2.48 (s, 3H), 2.52 (s, 3H), 3.29-3.38(m, 1H), 3.92 (s, 3H), 6.66 (s, 1H), 6.98 (s, 1H), 7.54 (s, 1H), 7.68(s, 1H). LC/MS (m/z): calcd. for C₂₂H₂₇N₅S (M+H)⁺: 394.3. found: 394.2.

Example 57 Preparation of4-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-tetrahydro-pyran-4-ol

To a −78° C. solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.60 g, 1.53 mmol) and THF (10 mL) is added 1.56 M n-Bu-Li (1.03 mL,1.61 mmol). After 30 minutes tetrahydro-pyran-4-one (0.21 mL, 2.29 mmol)is added over 5 minutes. The solution is stirred at −78° C. for 2 hours,warmed to ambient temperature, diluted with EtOAc (50 mL), washed withsat. NH₄Cl (50 mL), dried over MgSO₄, filtered and concentrated. Theresidue is purified by ISCO column chromatography (20%-100% EtOAc/hexanegradient) furnish the title compound (0.38 g, 0.92 mmol, 60%). ¹H NMR(CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 1.91-2.00 (m, 2H),2.11 (s, 3H), 2.20-2.30 (m, 2H), 2.46 (s, 3H), 2.51 (s, 3H), 3.30-3.39(m, 1H), 3.83-3.98 (m, 5H), 6.66 (s, 1H), 6.93 (s, 1H). LC/MS (m/z):calcd. for C₂₃H₃₁N₃O₂S (M+H)⁺: 414.3. found: 414.2.

Example 58 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(tetrahydro-pyran-4-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Method A.

To a solution of4-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-tetrahydro-pyran-4-ol(0.25 g, 0.604 mmol) and CH₂Cl₂ (10 mL) is added TFA (0.79 mL, 10.28mmol) and Et₃SiH (0.25 mL, 1.57 mmol). The solution is concentrated,dissolved in EtOAc (30 mL), washed with sat. NaHCO₃ (30 mL), dried overMgSO₄, filtered and concentrated. The residue is purified by ISCO columnchromatography (10%-15% EtOAc/hexane gradient), is dissolved in EtOH (25mL), 10% Pd/C (0.07 g, 0.066 mmol) is added and the solution stirredunder an atmosphere of H₂. After 2 hours the solution is filtered thruCelite® and concentrated. The residue is purified by ISCO columnchromatography (30% EtOAc in hexane) furnish the title compound (0.033g, 0.083 mmol, 14%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.95(m, 4H), 1.97-2.04 (m, 2H), 2.09 (s, 3H), 2.20-2.30 (m, 2H), 2.46 (s,3H), 2.52 (s, 3H), 3.00-3.11 (m, 1H), 3.30-3.40 (m, 1H), 3.54 (dt,J=11.8, 2.2 Hz, 2H), 4.08 (dd, J=11.8, 2.2 Hz, 2H), 6.65 (s, 1H), 6.75(s, 1H). LC/MS (m/z): calcd. for C₂₃H₃₁N₃OS (M+H)⁺: 398.7. found: 398.2.

Method B. A. 4-(5-Bromo-4-methyl-thiophen-2-yl)-tetrahydro-pyran-4-ol

To a −78° C. solution of 2-bromo-3-methyl-thiophene (2.0 g, 17.75 mmol)and THF (30 mL) is added 2.0 M LDA (9.32 mL, 18.63 mmol). After 30minutes at −78° C. tetrahydro-pyran-4-one (2.3 mL, 23.07 mmol) is addedand the solution is warmed to ambient temperature. The solution iswashed with sat. NH₄Cl (30 mL). The aqueous phases is extracted withEtOAc. The combined organic layers are dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(30%-100% EtOAc/hexane gradient) furnish the title compound (2.3 g, 8.30mmol, 47%). ¹H NMR (CDCl₃), δ 1.82 (m, 2H), 2.00 (s, 3H), 2.06-2.15 (m,3H), 2.16 (s, 3H), 3.77-3.84 (m, 2H), 3.87 dt, J=11.3, 2.2 Hz, 2H), 6.67(s, 1H). LC/MS (m/z): calcd. for C₁₀H₁₃BrO₂S (M+H)⁺: 277.0. found:260.9.

B. 4-(5-Bromo-4-methyl-thiophen-2-yl)-tetrahydro-pyran

To a solution of4-(5-bromo-4-methyl-thiophen-2-yl)-tetrahydro-pyran-4-ol (2.3 g, 8.30mmol) and 1,2-dichloroethane (50 mL) is added ZnI₂ (3.97 g, 12.45 mmol)and sodium cyanoborohydride (3.91, 62.23 mmol). The solution is stirredfor 1 hour, filtered thru celite and concentrated. The residue ispurified by ISCO column chromatography (5%-10% EtOAc/hexane gradient)furnish the title compound (1.53 g, 5.86 mmol, 71%). ¹H NMR (CDCl₃), δ1.69-1.82 (m, 2H), 1.84-1.92 (m, 2H), 2.14 (s, 3H), 2.84-2.98 (m, 1H),3.49 (dt, J=11.8, 2.2 Hz, 2H), 4.00-4.07 (m, 2H), 6.51 (s, 1H).

C.8-(1-Ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(tetrahydro-pyran-4-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25,4-(5-bromo-4-methyl-thiophen-2-yl)-tetrahydropyran (0.83 g, 3.19 mmol),1.56 M n-Bu-Li (2.04 mL, 3.19 mmol), ZnCl₂ (6.4 mL, 3.19 mmol),8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g,1.56 mmol) and Pd(PPh₃)₄ (0.092 g, 0.008 mmol) furnish the titlecompound (0.072 g, 0.18 mmol, 11%). Spectrum identical to that fromMethod A.

Example 59 Preparation of3-[5-(3,4-difluoro-phenyl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.50 g, 1.27 mmol) and PdCl₂(dppf) (0.047 g, 0.064 mmol) and 0.5 Msolution of 3,4-difluorophenylzinc bromide in THF (5.1 mL, 2.55 mmol)are reacted. The residue is purified by ISCO column chromatography(15%-20% EtOAc/hexane gradient) and is chromatographed (50×250 C18Symmetry column, 30-80% water: 0.1% TPA/ACN: 0.1% TFA gradient) furnishthe title compound (0.18 g, 0.42 mmol, 33%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 2.54 (s,3H), 3.31-3.40 (m, 1H), 6.69 (s, 1H), 7.13-7.21 (m, 1H), 7.18 (s, 1H),7.31-7.36 (m, 1H), 7.39-7.46 (m, 1H). LC/MS (m/z): calcd. forC₂₄H₂₅F₂N₃S (M+H)⁺: 426.3. found: 426.2.

Example 60 Preparation of3-(5-benzyl-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.765 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) and 0.5 Msolution of benzylzinc bromide in THF (4.6 mL, 2.29 mmol) are reacted.The residue is purified by ISCO column chromatography (15%-20%EtOAc/hexane gradient) and is chromatographed (50×250 C18 Symmetrycolumn, 40-65% water: 0.1% TFA/ACN: 0.1% TFA gradient) furnish the titlecompound (0.062 g, 0.15 mmol, 20%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz,6H), 1.73-1.92 (m, 4H), 2.06 (s, 3H), 2.45 (s, 3H), 2.51 (s, 3H),3.29-3.39 (m, 1H), 4.16 (s, 2H), 6.65 (s, 1H), 6.68 (s, 1H), 7.22-7.29(m, 1H), 7.31-7.36 (m, 4H). LC/MS (m/z): calcd. for C₂₅H₂₉N₃S (M+H)⁺:404.3. found: 404.2.

Example 61 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-4-pyridin-3-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

A solution of3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.64 mmol), pyridine-3-boronic acid (0.086 g, 0.70 mmol), 2 MNa₂CO₃ (0.48 mL, 0.96 mmol) and, n-PrOH (3 mL), is degassed withnitrogen for 10 minutes. Pd(OAc)₂ (2.7 mg, 0.0013 mmol) and PPh₃ (0.010g, 0.038 mmol) are added and the solution is heated at 90° C. overnight.The solution is diluted with EtOAc (30 mL), washed with 10% Na₂CO₃ (30mL), water (30 mL), brine (30 mL), dried over MgSO₄, filtered, andconcentrated. The residue is purified by ISCO (20-40% EtOAc gradient)furnish the title compound (0.051 g, 0.13 mmol, 20%). ¹H NMR (CDCl₃) δ0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.09 (s, 3H), 2.50 (s, 3H),2.52 (s, 3H), 3.29-3.40 (m, 1H), 6.69 (s, 1H), 7.33-7.43 (m, 1H), 7.47(s, 1H), 7.80 (d, J=7.9 Hz, 1H), 8.61 (bs, 1H), 8.78 (bs, 1H). LC/MS(m/z): calcd. for C₂₃H₂₆N₄S (M+H)⁺: 391.2. found: 391.4.

Example 62 Preparation of8-(1-ethyl-propyl)-3-[5-(6-methoxy-pyridin-2-yl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.765 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) and 0.5 Msolution of 6-methoxy-2-pyridylzinc bromide in THF (3.0 mL, 1.53 mmol)furnish the title compound (0.12 g, 0.29 mmol, 38%). ¹H NMR (CDCl₃), δ0.88 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.15 (s, 3H), 2.50 (s, 3H),2.51 (s, 3H), 3.29-3.38 (m, 1H), 3.98 (s, 3H), 6.61 (d, J=7.5 Hz, 1H),6.70 (s, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.56 (d, J=7.7 Hz,1H). LC/MS (m/z): calcd. for C₂₄H₂₈N₄OS (M+H)⁺: 421.3. found: 421.3.

Example 63 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(4-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.765 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) and 0.5 Msolution of 4-methyl-2-pyridylzinc bromide in THF (3.0 mL, 1.53 mmol)furnish the title compound (0.21 g, 0.52 mmol, 68%). ¹H NMR (CDCl₃), δ0.90 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.40 (s, 3H),2.52 (s, 6H), 3.30-3.40 (m, 1H), 6.67 (s, 1H), 6.97 (d, J=4.8 Hz, 1H),7.49 (s, 1H), 7.52 (s, 1H), 8.42 (d, J=4.8 Hz, 1H). LC/MS (m/z): calcd.for C₂₄H₂₈N₄S (M+H)⁺: 405.3. found: 405.3.

Example 64 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(3-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine)(0.30 g, 0.765 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) and 0.5 Msolution of 3-methyl-2-pyridylzinc bromide in THF (5.0 mL, 2.50 mmol)furnish the title compound (0.22 g, 0.54 mmol, 71%). ¹H NMR (CDCl₃), δ0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H),2.51 (s, 3H), 2.63 (s, 3H), 3.29-3.39 (m, 1H), 6.67 (s, 1H), 7.06-7.14(m, 1H), 7.44 (s, 1H), 7.74 (dd, J=7.5, 0.9 Hz, 1H), 8.47 (dd, J=4.9,0.9 Hz, 1H). LC/MS (m/z): calcd. for C₂₄H₂₈N₄S (M+H)⁺: 405.3. found:405.3.

Example 65 Preparation of(6-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyridin-2-yl)-dimethyl-amine

Using a procedure similar to Example 39, from Rieke® Zn in THF (0.20 g,3.06 mmol), (6-bromo-pyridin-2-yl)-dimethyl-amine (Newkomw et. el. J.Org. Chem., 1988, 3, 786) (0.41 mL, 2.04 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.35 g, 0.89 mmol), and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.16 g, 0.37 mmol, 36%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.15 (s, 3H), 2.51 (s, 3H), 2.52 (s,3H), 3.21 (s, 6H), 3.30-3.40 (m, 1H), 6.40 (d, J=8.4 Hz, 1H), 6.66 (s,1H), 6.95 (d, J=7.4 Hz, 1H), 7.45 (dd, J=8.4, 7.4 Hz, 1H), 7.46 (s, 1H).LC/MS (m/z): calcd. for C₂₅H₃₁N₅S (M+H)⁺: 434.3. found: 434.3.

Example 66 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(5-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.765 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol) and 0.5 Msolution of 4-methyl-2-pyridylzinc bromide in THF (3.0 mL, 1.53 mmol)furnish the title compound (0.23 g, 0.57 mmol, 74%). ¹H NMR (CDCl₃), δ0.90 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.16 (s, 3H), 2.35 (s, 3H),2.51 (s, 3H), 2.52 (s, 3H), 3.31-3.41 (m, 1H), 6.67 (s, 1H), 7.48 (s,1H), 7.50 (d, J=2.2 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 8.39-8.40 (m, 1H).LC/MS (m/z): calcd. for C₂₄H₂₈N₄S (M+H)⁺: 405.3. found: 405.3.

Example 67 Preparation of8-(1-ethyl-propyl)-3-[5-(6-methanesulfonyl-pyridin-2-yl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 2-Bromo-6-methanesulfonyl-pyridine

To a solution of 2-bromo-6-methylsulfanyl-pyridine (Testaferri et. elTetrahedron, 1985, 41, 1373) (2.15 g, 10.53 mmol) and CH₂Cl₂ (30 mL) isadded 56-87% mCPBA (12 g, 42.15 mmol). The solution is cooled with iceto ambient temperature and the solution is stirred for 2 hour, washedwith sat. Na₂S₂O₃ (15 mL), sat. NaHCO₃ (2×15 mL) dried over MgSO₄,filtered and concentrated. The residue is purified by recrystallizationfrom EtOAc/hexane furnish the title compound (1.71 g, 7.24 mmol, 69%).¹H NMR (CDCl₃), δ 3.26 (s, 3H), 7.73 (dd, J=8.0, 0.9 Hz, 1H), 7.82 (dd,J=8.0, 7.5 Hz, 1H), 8.05 (dd, J=7.5, 0.9 Hz, 1H). LC/MS (m/z): calcd.for C₆H₆BrNO₂S (M+H)⁺: 235.9. found: 235.9.

B.8-(1-ethyl-propyl)-3-[5-(6-methanesulfonyl-pyridin-2-yl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25,2-bromo-6-methanesulfonyl-pyridine (0.29 mL, 1.22 mmol), 1.3 M n-Bu-Li(0.82 mL, 1.07 mmol), ZnCl₂ (2.14 mL, 1.07 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.13 g, 0.28 mmol, 27%). ¹H NMR (CDCl₃), 60.88 (t, J=7.5Hz, 6H), 1.75-1.93 (m, 4H), 2.18 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H),3.30 (s, 3H), 3.30-3.38 (m, 1H), 6.70 (s, 1H), 7.64 (s, 1H), 7.83 (dd,J=7.6, 0.8 Hz, 1H), 7.89 (dd, J=7.9, 0.8 Hz, 1H), 7.93 (dd, J=7.9, 7.6Hz, 1H). LC/MS (m/z): calcd. for C₂₄H₂₈N₄O₂S₂ (M+H)⁺: 469.3. found:469.2.

Example 68 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-trifluoromethyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25,2-chloro-6-trifluoromethyl-pyridine (0.29 mL, 1.22 mmol), 1.34 M n-Bu-Li(0.80 mL, 1.07 mmol), ZnCl₂ (2.14 mL, 1.07 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.20 g, 0.44 mmol, 43%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.18 (s, 3H), 2.51 (s, 3H), 2.53 (s,3H), 3.30-3.40 (m, 1H), 6.69 (s, 1H), 7.50 (dd, J=7.5, 0.9 Hz, 1H), 7.65(s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.84 (dd, J=7.9, 7.5 Hz, 1H). LC/MS(m/z): calcd. for C₂₄H₂₅F₃N₄S (M+H)⁺: 459.3. found: 459.2.

Example 69 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-4-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a slurry of 0.05 g/mL of Reike® Zn in THF (3.0 mL, 2.29 mmol) isadded a solution of 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL).The solution was heated at 65° C. for 1 hour, cooled to ambienttemperature and the excess Zn allowed to settle for 1 hour. The solutionwas transferred to a flask containing3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(example Rupp-152) (0.32 g, 0.70 mmol) and PdCl₂(dppf) (0.028 g, 0.038mmol). The solution is heated at 65° C. overnight, diluted with EtOAc(30 mL), washed with sat. NH₄Cl (30 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO (50%-100% Et₂O) to furnishthe title compound (0.058 g, 0.15 mmol, 19%). ¹H NMR (CDCl₃) δ 0.86 (t,J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.11 (s, 3H), 2.47 (s, 3H), 2.49 (s,3H), 3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.68 (s, 1H), 7.64 (s, 1H), 7.99(s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₆N₆S (M+H)⁺: 395.2. found: 395.4.

Example 70 Preparation of1-(6-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyridin-2-yl)-ethanone

A.3-[5-(6-Bromo-pyridin-2-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25, 2,6-dibromo-pyridine (0.91 g,3.82 mmol), 1.34 M n-Bu-Li (1.50 mL, 2.00 mmol), ZnCl₂ (4.0 mL, 2.00mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.75 g, 1.92 mmol) and PdCl₂(dppf) (0.070 g, 0.096 mmol) furnish thetitle compound (0.26 g, 0.55 mmol, 29%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.4 Hz, 6H), 1.74-1.93 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 2.52 (s,3H), 3.30-3.39 (m, 1H), 6.68 (s, 1H), 7.31 (dd, J=7.5, 1.3 Hz, 1H),7.49-7.57 (m, 2H), 7.58 (s, 1H).

B.1-(6-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-pyridin-2-yl)-ethanone

To a −78° C. solution of3-[5-(6-bromo-pyridin-2-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine)(0.26 g, 0.55 mmol), and THF (5 mL), is added 1.34 M n-Bu-Li (0.43 mL,0.58 mmol). After 30 minutes N-methoxy-N-methyl-acetamide (0.065 mL,0.61 mmol) is added and the solution warmed to ambient temperature. Thesolution is diluted with EtOAc (30 mL), washed with sat. NH₄Cl (25 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO column chromatography (15-20% EtOAc/hexane gradient) furnish thetitle compound (0.030 g, 0.069 mmol, 13%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.19 (s, 3H), 2.52 (s, 3H), 2.53 (s,3H), 2.77 (s, 3H), 3.30-3.40 (m, 1H), 6.69 (s, 1H), 7.59 (s, 1H),7.77-7.85 (m, 2H), 7.87 (dd, J=6.8, 2.2 Hz, 1H). LC/MS (m/z): calcd. forC₂₅H₂₈N₄OS (M+H)⁺: 433.3. found: 433.2.

Example 71 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(5-trifluoromethyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from2-bromo-5-trifluoromethyl-pyridine (2.14 mL, 1.07 mmol), 1.34 M n-Bu-Li(0.80 mL, 1.07 mmol), ZnCl₂ (2.14 mL, 1.07 mmol),3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish thetitle compound (0.17 g, 0.37 mmol, 36%). ¹H NMR (CDCl₃), δ 0.90 (t,J=7.3 Hz, 6H), 1.76-1.94 (m, 4H), 2.18 (s, 3H), 2.19 (s, 3H), 2.53 (s,3H), 3.31-3.40 (m, 1H), 6.70 (s, 1H), 7.63 (s, 1H), 7.74 (d, J=8.4 Hz,1H), 7.78 (dd, J=8.4, 2.2 Hz, 1H), 7.79-7.82 (m, 1H). LC/MS (m/z):calcd. for C₂₄H₂₅F₃N₄S (M+H)⁺: 459.3. found: 459.2.

Example 72 Preparation of8-(1-ethyl-propyl)-3-(5-methoxymethyl-3-methyl-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol) and THF (3 mL) is added 1.34 M n-Bu-Li (0.50 mL,0.80 mmol). After 30 minutes iodo-methoxy-methane (0.097 mL, 1.15 mmol)is added and the solution warmed to ambient temperature. After 1 hourthe solution is diluted with EtOAc (40 mL) washed with water (30 mL),brine (30 mL), dried over MgSO₄, filtered and concentrated. The residueis purified by ISCO column chromatography (15%-20% EtOAc/hexanegradient) furnish the title compound (0.12 g, 0.34 mmol, 44%). ¹H NMR(CDCl₃), δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.09 (s, 3H), 2.45(s, 3H), 2.49 (s, 3H), 3.28-3.37 (m, 1H), 3.44 (s, 3H), 4.61 (s, 2H),6.65 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C₂₀H₂₇N₃OS (M+H)⁺:358.3. found: 358.3.

Example 73 Preparation of3-[5-(2-ethoxy-ethyl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 72, from of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol), 1.34 M n-Bu-Li (0.53 mL, 0.84 mmol),1-bromo-2-ethoxy-ethane (0.13 mL, 1.15 mmol) and KI (0.013 g, 0.076mmol) furnish the title compound (0.11 g, 0.29 mmol, 38%). ¹H NMR(CDCl₃), δ 0.86 (t, J=7.5 Hz, 6H), 1.23 (t, J=7.0 Hz, 3H), 1.72-1.90 (m,4H), 2.06 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 3.09 (t, J=7.0 Hz, 2H),3.28-3.37 (m, 1H), 3.55 (q, J=7.0 Hz, 2H), 3.71 (t, J=7.0 Hz, 2H), 6.64(s, 1H), 6.77 (s, 1H). LC/MS (m/z): calcd. for C₂₂H₃₁N₃OS (M+H)⁺: 386.3found: 386.3.

Example 74 Preparation of{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-phenyl-methanol

A. (5-Bromo-4-methyl-thiophen-2-yl)-phenyl-methanol

To a −78° C. solution of 2-bromo-3-methyl-thiophene (4.7 g, 26.54 mmol)and Et₂O (100 mL) is added 2.0 M LDA (14.6 mL, 29.2 mmol). After 1 hourbenzaldehyde (3.0 mL, 29.2 mmol) is added and the solution warmed toambient temperature and stirred for 2 hour. The solution is washed withsat. NH₄Cl (75 mL), dried over MgSO₄, filtered and concentrated. Theresidue is purified by ISCO column chromatography (20%-30% EtOAc/hexanegradient) furnish the title compound (3.29 g, 11.62 mmol, 44%). ¹H NMR(CDCl₃), δ 2.11 (s, 3H), 3.38-3.46 (m, 1H), 5.90 (s, 1H), 6.54 (s, 1H),7.30-7.45 (m, 5H). LC/MS (m/z): calcd. for C₁₂H₁₁BrOS (M+H)⁺: 281.0,283.0. found: 264.9, 266.9.

B.{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-phenyl-methanol

Using a procedure analogous to Example 30C, from 3-(5-boronicacid-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.1.15 mmol), (5-bromo-4-methyl-thiophen-2-yl)-phenyl-methanol(0.33 g, 1.15 mmol), 2 M Na₂CO₃ (0.86 mL, 1.72 mmol) n-PrOH (1 mL),Pd(OAc)₂ (0.0052 g, 0.023 mmol), and PPh₃ (0.018, 0.069 mmol). Theresidue is purified by ISCO column chromatography (20%-30% EtOAc/hexanegradient) and is chromatographed (50×250 C18 Symmetry column, 25-70%water: 0.1% TFA/ACN: 0.1% TFA gradient) furnish the title compound(0.017 g, 0.041 mmol, 3.5%). ¹H NMR (CDCl₃), δ 0.86 (t, J=7.5 Hz, 6H),1.72-1.90 (m, 4H), 2.04 (s, 3H), 2.43 (s, 3H), 2.49 (s, 3H), 2.75 (bs,1H), 3.26-3.38 (m, 1H), 6.05 (s, 1H), 6.65 (s, 1H), 6.76 (s, 1H),7.30-7.45 (m, 3H), 7.50-7.56 (m, 1H). LC/MS (m/z): calcd. for C₂₅H₂₉N₃OS(M+H)⁺: 420.3. found: 420.3.

Example 75 Preparation of3-(4,5-dibromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(4.00 g, 10.20 mmol) and AcOH (40 mL) is added Br₂ (0.57 mL, 11.21 mmol)and the solution heated at 110° C. overnight. Br₂ (0.57 mL, 11.21 mmol)is added and the solution heated at 110° C. for 2 hours. The solution ispoured into 5 M NaOH (200 mL) and ice (200 mL). The slurry is extractedwith EtOAc (2×150 mL). The combined organic layers are washed with water(200 mL), 20% NaHSO₃ (200 mL), sat. NaHCO₃ (200 mL) dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO (5%-15% EtOAcgradient) furnish the title compound (2.66 g, 5.64 mmol, 55%). ¹H NMR(CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.72-1.91 (m, 4H), 2.12 (s, 3H), 2.43(s, 3H), 2.50 (s, 3H), 3.25-3.35 (m, 1H), 6.69 (s, 1H). LC/MS (m/z):calcd. for C₁₈H₂₁Br₂N₃S (M+H)⁺: 470.0. found: 470.3.

Example 76 Preparation of3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(4,5-dibromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.22 g, 0.47 mmol) and THF (3 mL) is added 1.6 M n-BuLi (0.31 mL, 0.49mmol). After 20 minutes the solution is quenched with water (1 mL),warmed to ambient temperature, diluted with EtOAc (30 mL), washed withbrine (30 mL), dried over MgSO₄, filtered and concentrated. The residueis purified by ISCO (5%-10% EtOAc gradient) furnish the title compound(0.056 g, 0.14 mmol, 31%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H),1.73-1.93 (m, 4H), 2.09 (s, 3H), 2.44 (s, 3H), 2.49 (s, 3H), 3.27-3.36(m, 1H), 6.68 (s, 1H), 7.44 (s, 1H). LC/MS (m/z): calcd. for C₁₈H₂₂BrN₃S(M+H)⁺: 392.2. found: 392.3.

Example 77 Preparation of3-{2,6-Dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-pentan-3-ol

A. 2-(5-Bromo-4-methyl-thiophen-2-yl)-6-methyl-pyridine

To a −78° C. solution of 2-bromo-3-methyl-thiophene (2.0 mL, 17.75 mmol)and THF (30 mL) is added 2.0 M LDA (9.76 mL, 19.52 mmol). After 45minutes 0.5 M ZnCl₂ (39.0 mL, 19.50 mmol) is added and the solutionstirred for 30 minutes. 2-Bromo-6-methyl-pyridine (2.4 mL, 21.29 mmol)and Pd(PPh₃)₄ (0.50 g, 0.44 mmol) is added and the solution is warmed toambient temperature and stirred for 2 hour. The solution is washed withsat. NH₄Cl (20 mL). The aqueous layer is extracted with CH₂Cl₂ (30 mL).The combined organic layers are washed with sat. NH₄Cl (20 mL), driedover Na₂SO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (10%-20% EtOAc/hexane gradient) furnish the titlecompound (2.34 g, 8.73 mmol, 49%). ¹H NMR (CDCl₃), δ 2.21 (s, 3H), 2.54(s, 3H), 6.99 (d, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.33 (d, J=7.9 Hz, 1H),7.53 (dd, J=7.9, 7.9 Hz, 1H). LC/MS (m/z): calcd. for C₁₁H₁₀BrNS (M+H)⁺:267.0, 269.0. found: 267.7, 269.5.

B.2,6-Dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

A solution of 2,6-dimethyl-imidazo[1,2-b]pyridazine (below) (0.50 g,3.39 mmol), 2-(5-bromo-4-methyl-thiophen-2-yl)-6-methyl-pyridine (1.00g, 3.73 mmol), Cs₂CO₃ (2.32 g, 7.13 mmol) and DMF (5 mL) is de-gassedfor 15 minutes with N₂. Pd₂(dba)₃ (0.15 g, 0.16 mmol) and PPh₃ (0.17 g,0.65 mmol) is added and the solution is heated at 130° C. overnight. Thesolution is diluted with CH₂Cl₂ (30 mL) washed with water (2×25 mL),brine (25 mL) dried over MgSO₄, filtered and concentrated. The residueis purified by ISCO column chromatography (100% EtOAc), followed byrecrystallization from acetonitrile/water furnish the title compound(0.45 g, 1.35 mmol, 39%). ¹H NMR (CDCl₃), δ 2.13 (s, 3H), 2.50 (s, 3H),2.53 (s, 3H), 2.57 (s, 3H), 6.90 (d, J=9.2 Hz, 1H), 7.01 (d, J=7.5 Hz,1H), 7.46 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.56 (dd, J=8.0, 7.5 Hz, 1H),7.77 (d, J=9.2 Hz, 1H). LC/MS (m/z): calcd. for C₁₉H₁₈N₄S (M+H)⁺: 335.1.found: 335.1.

C.1-{2,6-Dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-propan-1-one

To a −78° C. solution of2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine(0.34 g, 1.02 mmol) and THF (9 mL) is added 2.0 M LDA (0.61 mL, 1.22mmol). After 3 minutes, N-methoxy-N-methyl-propionamide (Wolberg et. el.Chem. Eur. J., 2001, 7, 4562) (1.17 g, 1.42 mmol) is added and thesolution stirred for 20 minutes, warmed to ambient temperature andstirred for 30 minutes. The solution is diluted with EtOAc (50 mL)washed with sat. NH₄Cl (30 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(20%-30% EtOAc/hexane gradient) furnish the title compound (0.10 g, 0.26mmol, 25%). ¹H NMR (CDCl₃), δ 1.28 (t, J=7.0 Hz, 3H), 2.13 (s, 3H), 2.54(s, 3H), 2.58 (s, 6H), 3.59 (q, J=7.0 Hz, 2H), 7.03 (d, J=7.5 Hz, 1H),7.33 (s, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.55 (bs, 1H), 7.58 (dd, J=7.9,7.5 Hz, 1H). LC/MS (m/z): calcd. for C₂₂H₂₂N₄OS (M+H)⁺: 391.2. found:391.2.

D.3-{2,6-Dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-pentan-3-ol

To a −0° C. solution of1-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-propan-1-one(0.040 g, 0.10 mmol) and Et₂O (5 mL) is added 3.0 M ethyl magnesiumbromide (0.68 mL, 2.05 mmol). The solution is warmed to ambienttemperature, diluted with EtOAc (30 mL) washed with sat. NH₄Cl (20 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish thetitle compound (0.016 g, 0.038 mmol, 37%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.4 Hz, 6H), 1.92-2.01 (m, 4H), 2.14 (s, 3H), 2.46 (s, 3H), 2.53 (s,3H), 3.57 (s, 3H), 6.39 (s, 1H), 6.66 (s, 1H), 7.01 (d, J=7.5 Hz, 1H),7.46 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.57 (dd, J=7.9, 7.5 Hz, 1H).LC/MS (m/z): calcd. for C₂₄H₂₈N₄OS (M+H)⁺: 421.3. found: 421.3.

Example 78 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-4-thiazol-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To a flask containing3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.64 mmol) and PdCl₂(dppf) (0.023 g, 0.032 mmol) is added a 0.5M solution of 2-thiazolylzinc bromide (3.82 mL, 1.91 mmol). The solutionis heated at 65° C. overnight, diluted with EtOAc (30 mL), washed withsat. NH₄Cl (25 mL), dried over MgSO₄, filtered and concentrated. Theresidue is purified by ISCO (15%-20% EtOAc gradient) furnish the titlecompound (0.19 g, 0.48 mmol, 76%). ¹H NMR (CDCl₃) δ 0.88 (t, J=7.5 Hz,6H), 1.75-1.92 (m, 4H), 2.36 (s, 3H), 2.47 (s, 3H), 2.50 (, 3H),3.29-3.39 (m, 1H), 6.69 (s, 1H), 7.33 (d, J=3.3 Hz, 1H), 7.89 (d, J=3.3Hz, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₄N₄S₂ (M+H)⁺: 397.2.found: 397.3.

Example 79 Preparation of8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-o-tolyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using the procedure analogous to Example 32,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.15 g, 0.38 mmol) and PdCl₂(dppf) (0.014 g, 0.019 mmol) and 0.5Msolution of 2-methylphenylzinc iodide in THF (3 mL, 1.53 mmol) furnishthe title compound (0.069 g, 0.17 mmol, 46%). ¹H NMR (CDCl₃) δ 0.90 (t,J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.19 (s, 3H), 2.53 (s, 3H), 2.54 (s,3H), 2.55 (s, 3H), 3.32-3.40 (m, 1H), 6.68 (s, 1H), 7.02 (s, 1H),7.22-7.30 (m, 3H), 7.48-7.53 (m, 1H). LC/MS (m/z): calcd. for C₂₅H₂₉N₃S(M+H)⁺: 404.3. found: 404.3.

Example 80 Preparation of{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-2-yl}-phenyl-methanone

To a −78° C. solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol) and THF (5 mL) is added 1.30 M n-Bu-Li (0.50 mL,0.80 mmol). After 30 minutes N-methoxy-N-methyl-benzamide (0.13 mL, 0.84mmol) is added, the solution is warmed to ambient temperature, andstirred overnight. The solution is diluted with EtOAc (20 mL), washedwith sat. NH₄Cl (15 mL), water (15 mL), brine (15 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO columnchromatography (15%-20% EtOAc/hexane gradient) furnish the titlecompound (0.066 g, 0.16 mmol, 21%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.4 Hz,6H), 1.74-1.93 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H),3.29-3.38 (m, 1H), 6.71 (s, 1H), 7.49-7.54 (m, 2H), 7.56 (s, 1H),7.57-7.62 (m, 1H), 7.89-7.94 (m, 2H). LC/MS (m/z): calcd. for C₂₅H₂₇N₃OS(M+H)⁺: 418.2. found: 418.2.

Example 81 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-oxazol-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To a −78° C. solution of oxazole (0.14 g, 2.04 mmol) and THF (3 mL) isadded 1.6 M t-Bu-Li in hexane (1.32 mL, 2.14 mmol). The mixture isstirred at −78° C. for 15 minutes. 0.5 M ZnCl₂ in THF (4.3 mL, 2.14mmol) is added and the solution warmed to ambient temperature.3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) is added andmixture is stirred at 65° C. overnight, diluted with EtOAc (30 mL),washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (20% EtOAc/hexane gradient) and is chromatographed(50×250 C18 Symmetry column, 20-70% water: 0.1% TFA/ACN: 0.1% TFAgradient) to furnish the title compound (0.020 g, 0.053 mmol, 5%). ¹HNMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H),2.49 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.69 (s, 1H), 7.19 (s,1H), 7.59 (s, 1H), 7.65 (s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₄N₄OS(M+H)⁺: 381.3. found: 381.1.

Example 82 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(5-methyl-furan-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a 0° C. mixture of 2-methylfuran (0.18 mL, 2.04 mmol) and Et₂O (2 mL)is added 1.6 M t-Bu-Li in hexane (1.30 mL, 2.14 mmol). The mixture isheated at a reflux for 30 minutes, cooled to 0° C., and 0.5 M ZnCl₂ inTHF (4.3 mL, 2.14 mmol) is added and the solution warmed to ambienttemperature.3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) is added andmixture is stirred at 65° C. overnight, diluted with EtOAc (30 mL),washed with 10% citric acid (15 mL), water (15 mL), brine (15 mL), driedover MgSO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (20% EtOAc/hexane gradient) furnish the titlecompound (0.20 g, 0.51 mmol, 50%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz,6H), 1.74-1.92 (m, 4H), 2.12 (s, 3H), 2.35 (s, 3H), 2.48 (s, 3H), 2.51(s, 3H), 3.29-3.38 (m, 1H), 6.62 (dd, J=3.1, 0.9 Hz, 1H), 6.40 (d, J=3.1Hz, 1H), 6.66 (s, 1H), 7.12 (s, 1H). LC/MS (m/z): calcd. for C₂₃H₂₇N₃OS(M+H)⁺: 394.3. found: 394.2.

Example 83 Preparation of3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask of 2-bromo-3-chloro-thiophene (Lemaire et. el., Synth.Commun., 1994, 24, 95) (2.53 g, 12.82 mmol) is added 0.05 g/mL Reike®zinc in THF (25 mL, 19.24 mmol). The solution is heated at a reflux for2 hours. The excess zinc is allowed to settle and the solutiontransferred to a flask containing8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (exampleKW1-A03735-193) (2.01 g, 6.41 mmol) and PdCl₂(dppf) (0.23 g, 0.32 mmol).The solution is heated at a reflux overnight, quenched with sat. NH₄Cl(25 mL) and extracted with EtOAc (2×25 mL). The combined organic layersare dried over MgSO₄, filtered and concentrated. The residue is purifiedby ISCO column chromatography (2%-15% EtOAc/hexane gradient) furnish thetitle compound (1.32 g, 6.68 mmol, 62%). ¹H NMR (CDCl₃), δ 0.87 (t,J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.48 (s, 3H), 2.49 (s, 3H), 3.37-3.36(m, 1H), 6.67 (s, 1H), 7.07 (d, J=5.4 Hz, 1H), 7.48 (d, J=5.4 Hz, 1H).LC/MS (m/z): calcd. for C₁₇H₂₀ClN₃S (M+H)⁺: 334.1. found: 334.1.

Example 84 Preparation of3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine.(1.15 g, 3.44 mmol) and CH₂Cl₂ (12 mL) is added NBS (0.64 g, 3.62 mmol).The solution is stirred at ambient temperature overnight, washed withwater (2×75 mL), brine (75 mL), dried over Na₂SO₄, filtered andconcentrated to furnish the title compound (1.36 g, 3.29 mmol, 96%). ¹HNMR (CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.49 (s, 3H),2.53 (s, 3H), 3.26-3.36 (m, 1H), 6.70 (s, 1H), 7.07 (s, 1H). LC/MS(m/z): calcd. for C₁₇H₁₉BrClN₃S (M+H)⁺: 412.1. found: 412.0.

Example 85 Preparation of3-[3-chloro-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Method A.

To a flask of3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.73 mmol) and PdCl₂(dppf) (0.027 g, 0.036 mmol) is added 0.5 Msolution of 6-methyl-2-pyridylzinc bromide in THF (2.9 mL, 1.45 mmol).The mixture is stirred at 65° C. overnight, diluted with EtOAc (50 mL),washed with sat. NH₄CL (40 mL), water (40 mL), brine (40 mL), dried overMgSO₄, filtered and concentrated. The residue is purified by ISCO columnchromatography (20%-40% EtOAc/hexane gradient) furnish the titlecompound (0.072 g, 0.17 mmol, 23%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz,6H), 1.75-1.93 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.58 (s, 3H),3.30-3.39 (m, 1H), 6.70 (s, 1H), 7.06 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.7Hz, 1H), 7.54 (s, 1H), 7.60 (dd, J=7.7, 7.5 Hz, 1H). LC/MS (m/z): calcd.for C₂₃H₂₅ClN₄S (M+H)⁺: 425.2. found: 425.2.

Method B. A. 2-(4-Chloro-thiophen-2-yl)-6-methyl-pyridine

To a solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén ChemicaScripta, 1971, 1, 33) (1.50 g, 7.60 mmol) and 0.5 M solution of6-methyl-2-pyridylzinc bromide in THF (23.00 mL, 11.39 mmol) is addedPd(PPh₃)₄ (0.18 g, 0.15 mmol). The solution is heated at 40° C.overnight, diluted with Et₂O (50 mL), washed with sat. NH₄Cl (40 mL),dried over MgSO₄, filtered on concentrated. The residue is purified byISCO column chromatography (5%-20% EtOAc/hexane gradient) furnish thetitle compound (0.45 g, 2.15 mmol, 28%). ¹H NMR (CDCl₃), δ 2.56 (s, 3H),7.02 (d, 7.7 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H),7.39 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.9, 7.7, 1H).

B. 2-(5-bromo-4-chloro-thiophen-2-yl)-6-methyl-pyridine

To a 0° C. solution of 2-(4-chloro-thiophen-2-yl)-6-methyl-pyridine(example Rupp-96) (0.45 g, 1.45 mmol) and CH₂Cl₂ (10 mL) is added Br₂(0.15 mL, 2.91 mmol). The solution is warmed to ambient temperature andstirred for 1 hour. The solution is washed with sat. NaHCO₃ (10 mL),sat. Na₂S₂O₃ (10 mL), dried over MgSO₄, filtered and concentrated tofurnish the title compound (0.59 g, 2.04, 95%). ¹H NMR (CDCl₃), δ 2.55(s, 3H), 7.05 (d, 7.9 Hz, 1H), 7.29 (s, 1H), 7.34 (d, J=7.9 Hz, 1H),7.58 (dd, J=7.9, 7.9, 1H). LC/MS (m/z): calcd. for C₁₀H₇BrClNS (M+H)⁺:288.0. found: 287.9.

C.3-[3-Chloro-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A solution of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.39 g, 1.78 mmol),2-(5-bromo-4-chloro-thiophen-2-yl)-6-methyl-pyridine (0.59 g, 2.04mmol), Cs₂CO₃ (1.23 g, 3.77 mmol), and DMF (5 mL), is de-gassed with N₂for 15 minutes. PPh₃ (0.089 g, 0.34 mmol) and Pd₂(dba)₃ (0.079 g, 0.86mmol) is added and the solution heated at 110° C. for 48 hours. Thesolution is diluted with EtOAc (30 mL), washed with sat. NH₄Cl (25 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO column chromatography (20%-30% EtOAc/hexane gradient) and ischromatographed (19×300 C18 Symmetry column, 20-45% water: 0.1% TFA/ACN:0.1% TFA gradient) furnish the title compound (0.078 g, 0.18 mmol, 10%).Spectrum identical to Method A.

Example 86 Preparation of3-(3-chloro-5-pyridin-3-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Method A.

A solution of3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.61 mmol), pyridine-3-boronic acid (0.082 g, 0.67 mmol), 2 MNa₂CO₃ (0.45 mL, 0.91 mmol) and, n-PrOH (1 mL), is degassed withnitrogen for 10 minutes. Pd(OAc)₂ (0.0027 g, 0.0012 mmol) and PPh₃(0.0095 g, 0.036 mmol) are added and the solution is heated at 88° C.overnight. The solution is diluted with EtOAc (15 mL), washed with water(10 mL), sat. NaHCO₃ (10 mL), dried over MgSO₄, filtered andconcentrated. Purified by ISCO column chromatography (15-40%EtOAc/hexane gradient) furnish the title compound (0.095 g, 0.23 mmol,38%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.53(s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.71 (s, 1H), 7.32-7.37 (m,2H), 7.85-7.90 (m, 1H), 8.57 (d, J=4.0 Hz, 1H), 8.89 (s, 1H). LC/MS(m/z): calcd. for C₂₂H₂₃ClN₄S (M+H)⁺: 411.2. found: 411.2.

Method B. A. 3-(4-Chloro-thiophen-2-yl)-pyridine

A solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén ChemicaScripta, 1971, 1, 33) (1.45 g, 7.34 mmol), pyridine-3-boronic acid (0.95g, 7.71 mmol), 2 M Na₂CO₃ (5.50 mL, 11.01 mmol) and, n-PrOH (3 mL), isdegassed with N₂ for 10 minutes. Pd(OAc)₂ (0.033 g, 0.15 mmol) and PPh₃(0.12 g, 0.44 mmol) are added and the solution is heated at 85° C. for48 hours, diluted with CH₂Cl₂ (50 mL), washed with 10% Na₂CO₃ (2×30 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish thetitle compound (0.74 g, 3.78 mmol, 51%). ¹H NMR (CDCl₃), δ 7.12-7.13 (m,1H), 7.20 (d, J=1.4 Hz, 1H), 7.31 (dd, J=8.0, 4.9 Hz, 1H), 7.78-7.82 (m,1H), 8.55 (d, J=4.9 Hz, 1H), 8.82 (d, J=2.2 Hz, 1H).

B. 3-(5-Bromo-4-chloro-thiophen-2-yl)-pyridine

Using a procedure similar to Example 85 Method B. step B,3-(4-chloro-thiophen-2-yl)-pyridine (0.74 g, 3.78 mmol), and Br₂ (0.39mL, 7.56 mmol) furnish the title compound (0.99 g, 3.61 mmol, 95%). ¹HNMR (CDCl₃), δ 7.13 (s, 1H), 7.34 (dd, J=8.1, 4.4 Hz, 1H), 7.74-7.78 (m,1H), 8.58 (d, J=4.4 Hz, 1H), 8.78 (s, 1H).

C.3-(3-Chloro-5-pyridin-3-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 85 Method B Step C, from8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 2.30mmol), 3-(5-bromo-4-chloro-thiophen-2-yl)-pyridine) (0.76 g, 2.76 mmol),Cs₂CO₃ (1.57 g, 4.83 mmol), PPh₃ (0.11 g, 0.44 mmol) and Pd₂(dba)₃ (0.10g, 0.11 mmol). The residue is purified by ISCO column chromatography(15%-30% EtOAc/hexane gradient) furnish the title compound (0.35 g, 0.85mmol, 37%). Spectrum identical to Method A.

Example 87 Preparation of3-[3-chloro-5-(4-fluoro-phenyl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 25,3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.61 mmol), 4-fluorophenylboronic acid (0.093 g, 0.67 mmol), 2M Na₂CO₃ (0.45 mL, 0.91 mmol), n-PrOH (2 mL), Pd(OAc)₂ (0.0068 g, 0.030mmol) and PPh₃ (0.016 g, 0.061 mmol) furnish the title compound (0.041g, 0.096 mmol, 16%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H), 1.76-1.94(m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.70 (s, 1H),7.07-7.13 (m, 2H), 7.22 (s, 1H), 7.54-7.60 (m, 2H). LC/MS (m/z): calcd.for C₂₃H₂₃ClFN₃S (M+H)⁺: 428.2. found: 428.1.

Example 88 Preparation of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Method A.

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.18 mL, 2.33 mmol)and THF (3 mL) is added a 1.56 M solution of n-Bu-Li in hexanes (1.49mL, 2.33 mmol). The solution is stirred at −78° C. for 30 minutes, 0.5 Msolution of ZnCl₂ in THF (4.70 mL, 2.33 mmol) is added and the solutionwarmed to ambient temperature.3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.32 g, 0.78 mmol) and PdCl₂(dppf) (0.028 g, 0.039 mmol) is added andthe solution heated at 60° C. for 2 days, diluted with EtOAc (50 mL),washed with sat. NH₄Cl (30 mL), water (30 mL), brine (30 mL), dried overMgSO₄, filtered and concentrated. The residue is purified by ISCO columnchromatography (20%-10% EtOAc/hexane gradient) furnish the titlecompound (0.19 g, 0.46 mmol, 59%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz,6H), 1.76-1.94 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.29-3.37 (m, 1H),4.16 (s, 3H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s, 1H). LC/MS (m/z):calcd. for C₂₀H₂₃ClN₆S (M+H)⁺: 415.2. found: 415.1.

Method B.

A 5-L reaction flask equipped with a cooling bath, air stirrer, gasdispersion tube and thermometer probe is charged with5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (162.0 g,0.745 moles), 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(250.1 g, 0.898 moles), NMP (800 mL), KOAc (366.0 g), TBABr (50.5 g),and additional NMP (700 mL) to form a mixture. While stirring, N₂ isbubbled through the mixture for 1 hour. A mixture of Pd(OAc)₂ (8.37 g)and TDBPP (24.56 g) are added in one portion, then heated to 120° C. for3 hours. The reaction is cooled to 50° C. and transferred to a 12 Lflask. The mixture is cooled to 20-25° C., then added de-ionized H₂O(3.5 L) is added dropwise to precipitate out a sticky solid thatgradually solidifies with stirring overnight. The solids are filtered,washed with de-ionized H₂O (2×2 L), and fried on the filter plate for30-60 minutes. The crude solids (595 g) are warmed in EtOAc (6.0 L) to30° C., then filtered through GFF paper to remove insolubles. Thefiltrate is dried over Na₂SO₄, treated with Darco (30.0 g), heated to35° C., filtered, and concentrated to give brown solids (432 g). Thecrude solids are eluted through a silica plug (1.0 kg) with CH₂Cl₂ (4.0L), followed by EtOAc (16.0 L). Similar fractions are combined andconcentrated under vacuum to approximately 6.0 L, then treated withDarco overnight with stirring. After filtering off the Darco through GFFpaper, the filtrate is concentrated to solids (336 g). The solids arecrystallized from EtOAc:heptane (1:2) to afford the title compound as apale yellow solid (187 g, 60.5%, >98% area-% by reverse phase: ZorbaxSB-C8, 4.6 mm×250 mm, 5 microns, UV=218 nm, flow rate 1.0 mL/min., oventemp. 25° C., isocratic=30% water (0.1% TFA) & 70% AcCN.

Example 89 Preparation of8-(1-Ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(3-methyl-3H-imidazol-4-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using the procedure analogous to Example 31,3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol), 1.34M n-Bu-Li (0.80 mL, 1.07 mmol), 0.5M ZnCl₂ inTHF (2.14 mL, 1.07 mmol), 5-iodo-1-methyl-1H-imidazole (0.24 g, 1.22mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish the title compound(0.061 g, 0.15 mmol, 15%). ¹H NMR (CDCl₃) δ 0.89 (t, J=7.4 Hz, 6H),1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 3.24-3.38(m, 1H), 3.61 (s, 3H), 6.68 (s, 1H), 7.02 (s, 1H), 7.23 (s, 1H), 7.55(s, 1H). LC/MS (m/z): calcd. for C₂₂H₂₇N₅S (M+H)⁺: 394.3. found: 394.2.

Example 90 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

A. 4,4,5,5-Tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane

A mixture of 3-bromo-2-methyl-thiophene (Saika et. el. Chem. Soc. Chem.Communication, 18, 1994, 2133; Steinkopf et. el.; Justus Liebigs Ann.Chem., 513, 1934, 281; 3.1 g, 17.51 mmol), DMSO (50 mL),4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (4.90 g,19.26 mmol), and KOAc (5.20 g, 52.58 mmol) is de-gassed with N₂ for 15minutes. PdCl₂(dppf) (0.70 g, 0.88 mmol) is added and the solutionstirred at ambient temperature overnight, then warmed to 85° C. for 3hours. The solution is diluted with water (200 mL), extracted with EtOAc(2×100 mL). The combined organic layers washed with water (2×200 mL),brine (200 mL) dried over MgSO₄, filtered and concentrated. The residueis purified by ISCO column chromatography (5%-20% EtOAc/hexane gradient)furnish the title compound (1.52 g, 6.78 mmol, 39%). ¹H NMR (CDCl₃), δ1.34 (s, 12H), 2.72 (s, 3H), 7.04 (d, J=5.0 Hz, 1H), 7.22 (d, 5.0 Hz,1H).

B. 2-Methyl-thiophene-3-boronic acid

To a solution of4,4,5,5-tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane(1.52 g, 6.78 mmol), acetone (15 mL) and water (15 mL) is added NaIO₄(2.90 g, 13.56 mmol). The solution is stirred at ambient temperature for24 hours, then heated to a reflux for 24 hours. The solution isconcentrated dissolved in EtOAc (1450 mL), washed with water (100 mL),dried over MgSO₄, filtered and concentrated to furnish the titlecompound (0.75 g, 5.49 mmol, 78%). ¹H NMR (CDCl₃), δ 2.93 (s, 3H), 7.10(d, J=5.3 Hz, 1H), 7.51 (d, 5.3 Hz, 1H).

C.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(2-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

(1.65 g, 4.80 mmol), 2-methyl-thiophene-3-boronic acid (0.75 g, 5.28mmol), 2 M Na₂CO₃ (3.60 mL, 7.20 mmol) and n-PrOH (20 mL) is degassedwith N₂ for 10 minutes. Pd(OAc)₂ (0.022 g, 0.096 mmol) PPh₃ (0.076 g,0.29 mmol) is added and the solution heated at 60° C. for 24 hours, thenheated at 90° C. for 24 hours. The solution is concentrated, diluted inEtOAc (50 mL) washed with 10% Na₂CO₃ (40 mL), water (40 mL), brine (40mL) dried over MgSO₄, filtered and concentrated. The residue is purifiedby ISCO column chromatography (10%-15% EtOAc/hexane gradient) furnishthe title compound (0.78 g, 2.49 mmol, 52%). ¹H NMR (CDCl₃), δ 0.89 (t,J=7.5 Hz, 6H), 1.74-1.94 (m, 4H), 2.38 (s, 3H), 2.44 (s, 3H), 2.50 (s,3H), 3.30-3.40 (m, 1H), 6.64 (s, 1H), 7.11 (d, J=5.3 Hz, 1H), 7.20 (d,J=5.3 Hz, 1H). LC/MS (m/z): calcd. for C₁₈H₂₃N₃S (M+H)⁺: 314.2. found:314.2.

Example 91 Preparation of3-(5-bromo-2-methyl-thiophen-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine.(0.76 g, 2.42 mmol) and CH₂Cl₂ (10 mL) is added NBS (0.60 g, 3.37 mmol).The solution is stirred at ambient temperature for 2 hours andconcentrated. The solution is dissolved in Et₂O (30 mL) washed withwater (3×30 mL), brine (30 mL) dried over MgSO₄, filtered andconcentrated to furnish the title compound (0.95 g, 2.42 mmol, >99%). ¹HNMR (CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.93 (m, 4H), 2.31 (s, 3H),2.42 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.04 (s,1H). LC/MS (m/z): calcd. for C₁₈H₂₂BrN₃S (M+H)⁺: 392.2. found: 392.1.

Example 92 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-5-phenyl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-2-methyl-thiophen-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.51 mmol) and PdCl₂(dppf) (0.019 g, 0.025 mmol) and 0.5 Msolution of phenylzinc iodide in THF (2.0 mL, 1.02 mmol). The residue ispurified by column chromatography (0-10% EtOAc/hexane gradient) and ischromatographed (50×250 C18 Symmetry column, 30-70% water: 0.1% TFA/ACN:0.1% TFA gradient) furnish the title compound (0.081 g, 0.21 mmol, 41%).¹H NMR (CDCl₃), δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.40 (s,3H), 2.48 (s, 3H), 2.52 (s, 3H), 3.32-3.41 (m, 1H), 6.66 (s, 1H),7.23-7.30 (m, 1H), 7.32 (s, 1H), 7.34-7.41 (m, 2H), 7.57-7.63 (m, 2H).LC/MS (m/z): calcd. for C₂₄H₂₇N₃S (M+H)⁺: 390.2. found: 390.2.

Example 93 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-5-thiazol-2-yl-thiophen-3-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-2-methyl-thiophen-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.51 mmol), 0.5 M 2-thiazolylzinc bromide in THF (8.1 mL, 4.05mmol) and PdCl₂(dppf) (0.019 g, 0.025 mmol) furnish the title compound(0.20 g, 0.50 mmol, >99%). ¹H NMR (CDCl₃), δ 0.87 (t, J=7.5 Hz, 6H),1.74-1.91 (m, 4H), 2.40 (s, 3H), 2.45 (s, 3H), 2.50 (s, 3H), 3.29-3.38(m, 1H), 6.60 (s, 1H), 7.22 (d, J=3.2 Hz, 1H), 7.52 (s, 1H), 7.75 (d,J=3.2 Hz, 1H). LC/MS (m/z): calcd. for C₂₁H₂₄N₄S₂ (M+H)⁺: 397.1. found:397.2.

Example 94 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[2-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-3-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 32, from3-(5-bromo-2-methyl-thiophen-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.24 g, 0.61 mmol) and PdCl₂(dppf) (0.022 g, 0.031 mmol) and 0.5 Msolution of 6-methyl-2-pyridylzinc bromide in THF (3.7 mL, 1.84 mmol)furnish the title compound (0.086 g, 0.21 mmol, 34%). ¹H NMR (CDCl₃), δ0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.39 (s, 3H), 2.46 (s, 3H),2.51 (s, 3H), 2.57 (s, 3H), 3.31-3.40 (m, 1H), 6.65 (s, 1H), 6.97 (d,J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.50-7.56 (m, 2H). LC/MS (m/z):calcd. for C₂₄H₂₈N₄ (M+H)⁺: 405.2. found: 405.2.

Example 95 Preparation of8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 74B, from of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.51 mmol), 5-pyrimidine boronic acid (0.076 g, 0.61 mmol), 2 MNa₂CO₃ (0.38 mL, 0.76 mmol), Pd(OAc)₂ (0.0023 g, 0.011 mmol), PPh₃(0.0080 g, 0.0031 mmol), and n-PrOH (2 mL) is furnished the titlecompound (0.084 g, 0.21 mmol, 42%). ¹H NMR (CDCl₃), δ 0.86 (t, J=7.5 Hz,6H), 1.72-1.91 (m, 4H), 2.17 (s, 3H), 2.48 (s, 3H), 2.51 (s, 3H),3.26-3.36 (m, 1H), 6.69 (s, 1H), 7.74 (s, 1H), 8.95 (s, 2H), 9.10 (s,1H). LC/MS (m/z): calcd. for C₂₂H₂₅N₅S (M+H)⁺: 392.3. found: 392.2.

Example 96 Preparation of3-[5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask of 4-iodo-3,5-dimethyl-isoxazole (0.34 g, 1.53 mmol) is addeda solution of Rieke® zinc 5 g/100 mL in THF (3 mL, 2.29 mmol). Theslurry is heated at a reflux for 4 hours, the zinc is allowed to settleand the solution transferred to a flask of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol) and PdCl₂(dppf) (0.028 g, 0.038 mmol). The solutionis heated at 50° C. overnight, diluted with EtOAc (20 mL), washed with0.1 M HCl (15 mL), water (15 mL), brine (15 mL) dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO columnchromatography (15%-30% EtOAc/hexane gradient) furnish the titlecompound (0.22 g, 0.54 mmol, 71%). ¹H NMR (CDCl₃), δ 0.92 (t, J=7.5 Hz,6H), 1.78-1.96 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.53 (s, 3H), 2.56(s, 3H), 2.61 (s, 3H), 3.33-3.42 (m, 1H), 6.72 (s, 1H), 6.98 (s, 1H).LC/MS (m/z): calcd. for C₂₃H₂₈N₄OS (M+H)⁺: 409.3. found: 409.2.

Example 97 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyrimidin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

A solution of3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol), 2-tributylstannanyl-pyrimidine (0.34 g, 0.92 mmol)and THF (5 mL) is de-gassed with N₂ for 10 minutes Triphenylarsine(0.047 g, 0.15 mmol) and Pd₂(dba)₃ (0.035 g, 0.038 mmol) is added andthe solution heated at 55° C. for 48 hours and concentrated. The residueis purified by ISCO column chromatography (15%-30% EtOAc/hexanegradient), dissolved in acetonitrile (20 mL), washed with hexane (3×20mL) and concentrated to furnished the title compound (0.097 g, 0.25mmol, 32%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.4 Hz, 6H), 1.74-1.92 (m, 4H),2.18 (s, 3H), 2.51 (s, 3H), 2.52 (s, 3H), 3.29-3.38 (m, 1H), 6.67 (s,1H), 7.08 (t, J=4.8, 1H), 7.93 (s, 1H), 8.69 (s, 2H). LC/MS (m/z):calcd. for C₂₂H₂₅N₅S (M+H)⁺: 392.3. found: 392.2.

Example 98 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine

A. 1,3,5-Trimethylpyrazole-4-boronic acid

To a dry flask is added 300 mg (1.59 mmol) of4-bromo-1,3,5-trimethylpyrazole to 4.0 ml THF. The mixture is cooled to−78° C. and 1 eq of n-BuLi (1.6 M) is added via syringe. The mixture isstirred 1.5 hrs, and 0.19 ml of trimethylborate (1.08 eq) is added. Thereaction mixture is stirred 2 hrs, allowing bath to reach −10° C., then1.5 ml of 5N HCl is added and stirred 30 minutes longer. The aqueouslayer is extracted 3 times with ethyl acetate. The combined organics aredried over MgSO4, filtered, and evaporated to an oil. The oil isdissolved in methanol/methylene chloride and re-evaporated. The residueis triturated with acetone/ethyl acetate then filtered to obtain titlecompound as a white solid 92.1 mg (37.6%). ¹H-NMR (DMSO-d₆): δ5.92 (s);3.72 (s, 3H); 2.34 (s, 3H); 2.26 (s, 3H) ppm.

B.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine

3-Iodo-2,6-dimethyl-8-(1-ethyl-propyl)-imidazo[1,2-b]pyridazine (200 mg,0.582 mmol), 1,3,5-trimethylpyrazole-4-boronic acid (233 mg, 1.53 mmol),Pd(PPh3)4 (13.4 mg, 0.01 mmol) are combined in a microwave pressuretube. Then 0.58 ml of 2N Na2CO3 and 3.0 ml ofdimethoxyethane/H20/ethanol (7:3:2) solution is added. The mixture ismicrowaved at 155° C. for 20 minutes. Water is added and the mixture isextracted four times with ethyl acetate. The combined organics are driedover MgSO4, filtered, then evaporated to a residue which ischromatographed using hexanes, then 1:1 hexanes:ethyl acetate, then 100%ethyl acetate to give the title compound (6.4%) as a yellow oil. 1H-NMR(DMSO-d₆): δ6.86 (s, 1H); 3.73 (s, 3H); 3.06-3.10 (m, 1H); 2.41 (s, 3H);2.22 (s, 3H); 2.03 (s, 3H); 1.93 (s, 3H); 1.74-1.83 (m, 4H); 0.77 (t,J=7.26 Hz, 6H) ppm. MS/ES+=327 (100%, M+2).

Example 99 Preparation of2,6-Dimethyl-8-(1-propyl-butyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine

3-Iodo-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (75 mg,0.20 mmol), 1,3,5-trimethylpyrazole-4-boronic acid (80 mg, 0.52 mmol),2N Na2CO3 solution (0.22 ml), and 5.0 mg (0.0004 mmol) of Pd(PPh3)4 arecombined in microwave pressure vessel with 1.5 ml ofdimethylether/H2O/ethanol (7:3:2) solution. The mixture is microwaved at140° C. for 25 minutes. The mixture is evaporated and chromatographed onsilica gel column using hexanes then 3:1 hexane:ethyl acetate, then 1:1hexane:ethyl acetate to give the title compound (22.8%) as a clear oil.¹H-NMR (DMSO-d₆): δ6.88 (s, 1H); 3.72 (s, 3H); 3.06-3.10 (m, 1H); 2.40(s, 3H); 2.21 (s, 3H); 2.02 (s, 3H); 1.92 (s, 3H); 1.60-1.76 (m, 4H);1.08-1.21 (m, 4H); 0.82 (t, J=7.49 Hz, 6H) ppm. MS/ES+354 (100%, M+1).

Example 100 Preparation of5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid dimethylamide

Using a procedure analogous to Example 23B,5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylicacid (151 mg, 0.42 mmol) and 2.0 M dimethylamine (2.0 mL, 4 mmol) givethe title compound (161 mg, 0.42 mmol, 100%). ¹H NMR (CDCl₃): δ 0.89 (t,J=7.4 Hz, 6H), 1.75-1.94 (m, 4H), 2.14 (s, 3H), 2.51 (s, 3H), 2.53 (s,3H), 3.15-3.50 (m, 7H), 6.72 (s, 1H), 7.30 (s, 1H). ES-MS (m/z): calcdfor C21H28N4OS (M+H)⁺: 385.6 found: 385.3.

Example 101 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(1-methyl-1H-Imidazol-3-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 31. from3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 1.02 mmol), 1.34 M n-BuLi (0.80 mL, 1.07 mmol), 0.5 M ZnCl₂ inTHF (2.14 mL, 1.07 mmol), 3-iodo-1-methyl-1H-imidazole (0.24 mL, 1.22mmol) and PdCl₂(dppf) (0.037 g, 0.051 mmol) furnish the title compound(0.030 g, 0.076 mmol, 8%). ¹H NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H),1.74-1.93 (m, 4H), 2.13 (s, 3H), 2.50 (s, 3H), 2.51 (s, 3H), 3.31-3.40(m, 1H), 3.72 (s, 3H), 6.66 (s, 1H), 7.09 (d, J=1.3 Hz, 1H), 7.19 (s,1H), 7.86 (d, J=1.3 Hz, 1H). LC/MS (m/z): calcd. for C₂₂H₂₇N₅S (M+H)⁺:394.2. found: 394.2.

Example 102 Preparation ofN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine,hydrochloride salt

IPA (225.0 mL) is added to compoundN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine(18.8 g, 0.0448 mmol, below) in a 1 L 1-neck round-bottomed flask Thestarting material slurry is heated to 50° C. on a Buchi bath, at whichtime a hazy solution resulted. Concentrated (12 M) aqueous HCl (3.73 mL,0.0448 mmole, 1.0 eq) is added all at once, and the hazy solution isstirred at 50° C. on the Buchi for 10 minutes, then evaporated to ayellow solid under vacuum. After 20 minutes at room temperature undervacuum (weight of 20.9 g), acetone (100 mL) is added and the resultingyellow slurry is stirred at room temperature for 1 hour, then cooledwith an ice bath and stirred for an additional 1 hour. The slurry isfiltered, rinsed with acetone, and dried overnight under vacuum at 40°C. to provide pale yellow-white crystalline solid 19.18 g (94%). ¹H NMR(DMSO): δ 7.52 (s, 1H), 3.73 (t, J=4.6, 4H), 3.49 (t, J=5.2 Hz, 4H),3.39 (m, 1H), 2.57 (s, 3H), 2.49 (s, 3H), 1.77 (m, 4H), 0.80 (t, J=7.4Hz, 6H).

Example 103 Preparation of8-(1-ethyl-propyl)-3-[5-(2-fluoro-phenyl)-3-methyl-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 30B, 3-(5-boronicacid-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.18 g, 0.50 mmol), 1-bromo-2-fluoro-benzene (0.072 g, 0.65 mmol), and2 M Na₂CO₃ (0.38 mL, 0.76 mmol), n-PrOH (2 mL), and Pd(PPh₃)₄ (0.029 g,0.025 mmol) furnish the title compound (0.022 g, 0.054 mmol, 11%). ¹HNMR (CDCl₃), δ 0.93 (t, J=7.4 Hz, 6H), 1.71-1.96 (m, 4H), 2.19 (s, 3H),2.66 (s, 3H), 2.67 (s, 3H), 3.41-3.50 (m, 1H), 7.15 (s, 1H), 7.15-7.23(m, 2H), 7.28-7.35 (m, 1H), 7.45 (d, J=1.4 Hz, 1H), 7.66 (dt, J=7.8, 1.6Hz, 1H). LC/MS (m/z): calcd. for C₂₄H₂₆FN₃S (M+H)⁺: 408.2. found: 408.2.

Example 104 Preparation of3-(3-chloro-5-pyrimidin-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 3-(3-Chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(2.0 g, 5.97 mmol) and THF (30 mL) is added 1.6 M n-BuLi (4.1 mL). After30 minutes B(OMe)₃ (0.74 mL, 6.59 mmol) is added, the solution is warmedto ambient temperature and stirred overnight. 1 M HCl (30 μL) is addedand the solution stirred for 20 minutes. The solution is made basic with5 M NaOH. The organic layer is extracted with 1 M NaOH (30 mL). Thecombined aqueous layers are made acidic with 5 M HCl, K₃PO₄.3H₂O isadded and the PH adjusted to 5.5 using 1 M NaOH. The combined aqueouslayers are extracted with EtOAc (200 mL), washed with brine (150 mL),dried over MgSO₄, filtered and concentrated to furnish the titlecompound (2.20 g, 5.82 mmol, 97%). LC/MS (m/z): calcd. forC₁₇H₂₁BClN₃O₂S (M+H)⁺: 378.7. found: 378.0.

B.3-(3-Chloro-5-pyrimidin-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A solution of 3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g,0.66 mmol), 2-bromo-pyrimidine (0.21 g, 1.32 mmol), 2 M Na₂CO₃ (0.66 mL,1.32 mmol), and i-PrOH (3 mL) are degassed with N₂ for 15 minutes.Pd(OAc)₂ (7.4 mg, 0.033 mmol) and PPh₃ (0.026 g, 0.099 mmol) are addedand the solution is heated at 90° C. overnight. The solution is dilutedwith EtOAc (35 mL), washed with 10% Na₂CO₃ (35 mL), brine (35 mL), driedover Na₂SO₄, filtered and concentrated. The residue is purified by ISCOcolumn chromatography (20%-30% EtOAc/hexane gradient) furnish the titlecompound (0.077 g, 0.19 mmol, 29%). ¹H NMR (CDCl₃) δ 0.88 (d, J=7.4 Hz,6H), 1.75-1.93 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.27-3.40 (m, 1H),6.71 (s, 1H), 7.16 (t, J=5.0 Hz, 1H), 8.00 (s, 1H), 8.74 (d, J=5.0 Hz,2H). LC/MS (m/z): calcd. for C₂₁H₂₂ClN₅S (M+H)⁺: 412.1. found: 412.2.

Example 105 Preparation of3-(3-chloro-5-thiazol-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 104,3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g,0.66 mmol), 2-bromo-pyrimidine (0.21 g, 1.32 mmol), 2 M Na₂CO₃ (0.66 mL,1.32 mmol) and i-PrOH (3 mL), Pd(OAc)₂ (7.4 mg, 0.033 mmol), and PPh₃(0.026 g, 0.099 mmol) furnish the title compound (0.099 g, 0.24 mmol,35%). ¹H NMR (CDCl₃) δ 0.88 (d, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.52(s, 3H), 2.53 (s, 3H), 3.28-3.38 (m, 1H), 6.71 (s, 1H), 7.33 (t, J=3.3Hz, 1H), 7.49 (s, 1H), 7.81 (d, J=3.3 Hz, 2H). LC/MS (m/z): calcd. forC₂₁H₂₂ClN₅S (M+H)⁺: 417.1. found: 417.1.

Example 106 Preparation of3-[3-chloro-5-(2-methyl-2H-pyrazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of 1-methyl-1H-pyrazole (0.12 g, 1.45 mmol) andTHF (4 mL) is added 1.6 M n-BuLi (0.91 mL, 1.45 mmol). After 45 minutes0.5 M ZnCl₂ (2.9 mL, 1.45 mmol) is added and the solution is warmed toambient temperature. After 30 minutes3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(example Rupp-88) (0.30 g, 0.73 mmol) and PdCl₂(dppf) (0.027 g, 0.036mmol) are added and the solution heated at 65° C. overnight, dilutedwith EtOAc (30 mL), washed with sat. NH₄Cl (2×30 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO columnchromatography (15%-30% EtOAc/hexane gradient) furnish the titlecompound (0.15 g, 0.36 mmol, 50%). ¹H NMR (CDCl₃) δ 0.88 (d, J=7.5 Hz,6H), 1.74-1.91 (m, 4H), 2.52 (s, 6H), 3.26-3.36 (m, 1H), 4.05 (s, 3H),6.45 (d, J=1.9 Hz, 1H), 6.71 (s, 1H), 7.14 (s, 1H), 7.49 (d, J=1.9 Hz,1H). LC/MS (m/z): calcd. for C₂₁H₂₄ClN₅S (M+H)⁺: 414.2. found: 414.2.

Example 107 Preparation of3-(3-chloro-5-pyridin-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 104,3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g,0.66 mmol), 4-bromo-pyridine hydrochloride (0.26 g, 1.32 mmol), 2 MNa₂CO₃ (1.00 mL, 1.99 mmol), i-PrOH (3 mL), Pd(OAc)₂ (7.4 mg, 0.033mmol), and PPh₃ (0.026 g, 0.099 mmol) furnish the title compound (0.16g, 0.59 mmol, 59%). ¹H NMR (CDCl₃) δ0.87 (d, J=7.5 Hz, 6H), 1.74-1.92(m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.27-3.36 (m, 1H), 6.72 (s, 1H),7.45-7.49 (m, 3H), 8.63 (d, J=1.3 Hz, 1H), 8.64 (d, J=1.3 Hz, 1H). LC/MS(m/z): calcd. for C₂₂H₂₃ClN₄S (M+H)⁺: 411.1. found: 411.1.

Example 108 Preparation of3-[3-chloro-5-(3,5-dimethyl-isoxazol-4-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 104,3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g,0.66 mmol), 4-iodo-3,5-dimethyl-isoxazole (0.30 g, 1.32 mmol), 2 MNa₂CO₃ (0.66 mL, 1.32 mmol) and i-PrOH (3 mL), Pd(OAc)₂ (7.4 mg, 0.033mmol), and PPh₃ (0.026 g, 0.099 mmol) furnish the title compound (0.14g, 0.50 mmol, 50%). ¹H NMR (CDCl₃) δ 0.87 (d, J=7.5 Hz, 6H), 1.73-1.92(m, 4H), 2.43 (s, 3H), 2.53 (s, 6H), 2.57 (s, 3H), 3.27-3.38 (m, 1H),6.71 (s, 1H), 7.01 (s, 1H). LC/MS (m/z): calcd. for C₂₂H₂₅ClN₄OS (M+H)⁺:429.2. found: 429.2.

Example 109 Preparation of3-(3-chloro-5-pyridin-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask containing3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.61 mmol) and PdCl₂(dppf) (0.022 g, 0.030 mmol) is added a 0.5M solution of 2-pyridylzinc bromide (2.40 mL, 1.21 mmol) and thesolution heated at 65° C. overnight, diluted with EtOAc (30 mL), washedwith sat. NH₄Cl (2×30 mL), dried over MgSO₄, filtered and concentrated.The residue is purified by ISCO column chromatography (20%-40%EtOAc/hexane gradient) followed by recrystallization from CH₃CN furnishthe title compound (0.15 g, 0.36 mmol, 60%). ¹H NMR (CDCl₃) δ 0.88 (d,J=7.5 Hz, 6H), 1.73-1.93 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.29-3.38(m, 1H), 6.70 (s, 1H), 7.17-7.23 (m, 1H), 7.56 (s, 1H), 7.66 (d, J=7.9Hz, 1H), 7.70-7.76 (m, 1H), 8.59 (d, J=4.7 Hz, 1H). LC/MS (m/z): calcd.for C₂₂H₂₃ClN₄S (M+H)⁺: 412.0. found: 412.4.

Example 110 Preparation of3-(3-chloro-5-pyrimidin-5-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 104,3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g,0.66 mmol), 4-bromo-pyrimidine (0.21 g, 1.32 mmol), 2 M Na₂CO₃ (0.66 mL,1.32 mmol), i-PrOH (3 mL), Pd(OAc)₂ (7.4 mg, 0.033 mmol), and PPh₃(0.026 g, 0.099 mmol) furnish the title compound (0.053 g, 0.13 mmol,20%). ¹H NMR (CDCl₃) δ 0.88 (d, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.53(s, 3H), 2.54 (s, 3H), 3.27-3.37 (m, 1H), 6.73 (s, 1H), 7.40 (s, 1H),8.97 (s, 2H), 9.18 (s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₂ClN₅S (M+H)⁺:412.1. found: 411.2.

Example 111 Preparation of3-(3-chloro-5-pyrazin-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 104,3-(3-chloro-thiophen-2-yl-5-boronicacid)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g,1.06 mmol), 2-iodo-pyrazine (0.16 g, 1.59 mmol), 2 M Na₂CO₃ (1.06 mL,2.12 mmol) and i-PrOH (5 mL), Pd(OAc)₂ (0.012 g, 0.053 mmol), and PPh₃(0.042 g, 0.16 mmol) furnish the title compound (0.15 g, 0.36 mmol,34%). ¹H NMR (CDCl₃) δ 0.87 (d, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.51(s, 3H), 2.52 (s, 3H), 3.25-3.37 (m, 1H), 6.71 (s, 1H), 7.66 (s, 1H),8.45 (d, J=2.6 Hz, 1H), 8.51-8.53 (m, 1H), 8.96 (d, J=1.0 Hz, 1H). LC/MS(m/z): calcd. for C₂₁H₂₂ClN₅S (M+H)⁺: 412.1. found: 412.3.

Example 112 Preparation of3-(3-chloro-5-thiazol-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a 0° C. solution of3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.60 g, 1.45 mmol) and THF (2 mL) is added 0.05 g/mL of Reike® Zn (3.80mL, 2.91 mmol). The solution is heated at a reflux for 1 hour, and theexcess Zn allowed to settle for 1 hour at ambient temperature. Thesolution is transferred to a flask of 4-bromo-thiazole (Kelly, T. et al.Tetrahedron, Lett. 1995, 51, 9293) (0.29 g, 1.74 mmol). PdCl₂(dppf)(0.027 g, 0.036 mmol) is added and the solution heated at 65° C.overnight, diluted with EtOAc (40 mL), washed with sat. NH₄Cl (30 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO column chromatography (15%-20% EtOAc/hexane gradient) followed byISCO column chromatography (100% Et₂O) to furnish the title compound(0.098 g, 0.24 mmol, 16%). ¹H NMR (CDCl₃) δ 0.88 (d, J=7.5 Hz, 6H),1.74-1.92 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.28-3.38 (m, 1H), 6.70(s, 1H), 7.45 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H).LC/MS (m/z): calcd. for C₂₀H₂₁ClN₄S₂ (M+H)⁺: 417.1. found: 417.3.

Example 113 Preparation of8-(1-ethyl-1-fluoro-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-pentan-3-ol(0.23 g, 0.55 mmol) and CH₂Cl₂ (3 mL) is added a solution of[bis(2-methoxyethyl)amino]sulfur triflouride (0.14 g, 0.60 mmol) andCH₂Cl₂ (2 mL). The solution is warmed to ambient temperature and stirredovernight. The solution is washed with sat. NaHCO₃ (5 mL) andconcentrated. The reside is purified by ISCO column chromatography(15%-20% EtOAc/hexane gradient) furnish the title compound (0.13 g, 0.31mmol, 57%). ¹H NMR (CDCl₃) δ 0.80 (t, J=7.5 Hz, 6H), 2.14 (s, 3H),2.16-2.31 (m, 2H), 2.46 (s, 3H), 2.54 (s, 3H), 2.56 (s, 3H), 2.59-2.70(m, 2H), 6.98 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H),7.52 (s, 1H), 7.56 (dd, J=7.8, 7.6 Hz, 1H). LC/MS (m/z): calcd. forC₂₄H₂₇FN₄S (M+H)⁺: 423.2. found: 423.4.

Example 114 Preparation of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile

To a solution 0.05 g/mL of Reike® Zn (31 mL, 23.93 mmol) is added2-bromo-thiophene-3-carbonitrile (Fournari, P. et al. Bull. Soc. Chim.Fr., 1967, 4115) (2.25 g, 11.96 mmol) and THF (5 mL). The solution isheated at a reflux for 2 hours, cooled to ambient temperature and theexcess Zn allowed to settle. The solution is transferred via a cannulainto a flask of8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.5 g,7.98 mmol) and PdCl₂(dppf) (0.29 g, 0.040 mmol). The mixture is heatedat 65° C. overnight, diluted with EtOAc (75 mL), washed with sat. NH₄Cl(2×75 mL), dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO column chromatography (10%-20% EtOAc/hexane gradient)furnish the title compound (1.10 g, 3.39 mmol, 42%). ¹H NMR (CDCl₃) δ0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.55 (s, 3H), 2.61 (s, 3H),3.25-3.34 (m, 1H), 6.75 (s, 1H), 7.35 (d, J=5.2 Hz, 1H), 7.53 (d, J=5.2Hz, 1H). LC/MS (m/z): calcd. for C₁₈H₂₀N₄S (M+H)⁺: 325.5. found: 325.2.

Example 115 Preparation of5-bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile

To a solution of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile(0.83 g, 2.56 mmol) and CH₂Cl₂ (10 mL) is added NBS (0.48 g, 2.69 mmol).The solution is stirred for 1 hour, diluted with Et₂O (100 mL), washedwith water (3×100 mL), brine (100 mL), dried (MgSO₄) filtered andconcentrated to furnish the title compound (1.03 g, 2.55 mmol, >99%). ¹HNMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.56 (s, 3H),2.60 (s, 3H), 3.24-3.32 (m, 1H), 6.76 (s, 1H), 7.30 (s, 1H). LC/MS(m/z): calcd. for C₁₈H₁₉BrN₄S (M+H)⁺: 404.4. found: 404.1.

Example 116 Preparation of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-thiazol-2-yl-thiophene-3-carbonitrile

To a flask containing5-bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile(0.25 g, 0.62 mmol) and PdCl₂(dppf) (0.023 g, 0.031 mmol) is added asolution of 0.5 M 2-thiazolylzinc bromide (6.0 mL, 3.10 mmol). Thesolution is heated at 65° C. overnight, diluted with EtOAc (30 mL),washed with sat. NH₄Cl (2×25 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(15%-20% EtOAc/hexane gradient) furnish the title compound (0.16 g, 0.39mmol, 64%). ¹H NMR (CDCl₃) δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H),2.58 (s, 3H), 2.66 (s, 3H), 3.25-3.35 (m, 1H), 6.78 (s, 1H), 7.38 (d,J=3.5 Hz, 1H), 7.70 (s, 1H), 7.84 (d, J=3.5 Hz, 1H). LC/MS (m/z): calcd.for C₂₁H₂₁N₅S₂ (M+H)⁺: 408.6. found: 408.1.

Example 117 Preparation of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-thiazol-2-yl-thiophene-3-carbonitrile

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.14 mL, 1.86 mmol)and THF (5 mL) is added a 1.6 M solution of n-BuLi in hexanes (1.20 mL,1.86 mmol) after 30 minutes a 0.5 M solution of ZnCl₂ in THF (4.70 mL,2.33 mmol) is added and the solution warmed to ambient temperature andstirred for 30 minute.5-Bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile(example Rupp-122) (0.25 g, 0.62 mmol) and PdCl₂(dppf) (0.023 g, 0.031mmol) is added and the solution heated at 65° C. overnight, diluted withEtOAc (25 mL), washed with sat. NH₄Cl (20 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO columnchromatography (15%-60% EtOAc/hexane gradient), and is chromatographed(50×250 C18 X-Terra RP column, 30-90% 10 mM NH₄HCO₃/water/5% ACN:ACNgradient). The residue is dissolved in Et₂O (25 mL), washed with sat.NaHCO₃ (25 mL), dried over MgSO4, filtered and concentrated to furnishthe title compound (0.013 g, 0.032 mmol, 5%). ¹H NMR (CDCl₃) δ 0.87 (t,J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.58 (s, 3H), 2.67 (s, 3H), 3.26-3.34(m, 1H), 4.17 (s, 3H), 6.79 (s, 1H), 6.78 (s, 1H), 7.92 (s, 1H). LC/MS(m/z): calcd. for C₂₁H₂₃N₇S (M+H)⁺: 406.5. found: 406.2.

Example 118 Preparation of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-(6-methyl-pyridin-2-yl)-thiophene-3-carbonitrile

To a flask containing5-bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile(0.25 g, 0.62 mmol) and PdCl₂(dppf) (0.024 g, 0.033 mmol) is added asolution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (2.50 mL, 1.24mmol). The solution is heated at 65° C. overnight, diluted with EtOAc(30 mL), washed with sat. NH₄Cl (2×30 mL), dried over MgSO₄, filteredand concentrated. The residue is purified by ISCO column chromatography(15%-25% EtOAc/hexane gradient), furnish the title compound (0.11 g,0.26 mmol, 39%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.76-1.92 (m,4H), 2.57 (s, 3H), 2.58 (s, 3H), 2.65 (s, 3H), 3.26-3.35 (m, 1H), 6.75(s, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.63 (dd,J=7.9, 7.5 Hz, 1H), 7.74 (s, 1H). LC/MS (m/z): calcd. for C₂₄H₂₅N₅S(M+H)⁺: 416.6. found: 416.2.

Example 119 Preparation of2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-5-pyridin-3-yl-thiophene-3-carbonitrile

To a −78° C. solution of 3-iodo-pyridine (0.32 g, 1.56 mmol), 0.5 MZnCl₂ in THF (3.20 mL, 1.59 mmol), and THF (2 mL) is added 1.7 M t-BuLi(1.85 mL, 3.15 mmol). The solution is warmed to ambient temperature andstirred for 30 minutes.5-Bromo-2-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophene-3-carbonitrile(0.21 g, 0.52 mmol) and Pd(PPh₃)₄ (0.03 g, 0.026 mmol) are added and thesolution heated at 55° C. for 1 hour, cooled to ambient temperature andstirred overnight, diluted with EtOAc (50 mL), washed with sat. NH₄Cl(2×40 mL), dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO column chromatography (15%-40% EtOAc/hexane gradient),furnish the title compound (0.15 g, 0.37 mmol, 71%). ¹H NMR (CDCl₃) δ0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.58 (s, 3H), 2.66 (s, 3H),3.26-3.35 (m, 1H), 6.78 (s, 1H), 7.34-7.46 (m, 1H), 7.56 (s 1H), 7.91(d, J=7.1 Hz, 1H), 8.62 (s, 1H), 8.91 (s, 1H). LC/MS (m/z): calcd. forC₂₃H₂₃N₅S (M+H)⁺: 402.6. found: 402.4.

Example 120 Preparation of3-(3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 2-Bromo-3,4-dimethyl-thiophene

To a solution of 3,4-dimethyl-thiophene (2.0 g, 17.82 mmol) (Minato et.al., Tetrahedron 1982, 38, 3347) in CH₂Cl₂ (20 mL) is added NBS (3.3 g,18.72 mmol). The solution is stirred for 1 hour, diluted with Et₂O (100mL), washed with water (3×100 mL), brine (100 mL), dried (MgSO₄)filtered and concentrated. The residue is purified by ISCO columnchromatography (100% hexane) furnish the title compound (3.0 g, 16.70mmol). ¹H NMR (CDCl₃) δ 2.10 (s, 3H), 2.17 (s, 3H), 6.85 (s, 1H).

B.3-(3,4-Dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineand8-(1-ethyl-propyl)-2,6-dimethyl-3-(3,4,3′,4′-tetramethyl-[2,2′]bithiophenyl-5-yl)-imidazo[1,2-b]pyridazine,respectively

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.30 g, 10.58mmol), 2-bromo-3,4-dimethyl-thiophene (3.03 g, 15.88 mmol) and Cs₂CO₃(7.24 g, 22.23 mmol) and DMF (50 mL) is de-gassed with N₂ for 20minutes. Pd₂(dba)₃ (0.48 g, 0.053 mmol) and PPh₃ (0.56 g, 0.21 mmol) areadded and the solution is heated at 120° C. overnight. The solution isdiluted with EtOAc (200 mL), washed with water (3×200 mL), brine (200mL), dried (MgSO₄), filtered and concentrated. The residue is purifiedby ISCO column chromatography (10%-15% EtOAc/hexane gradient) furnish2.04 g of a brown oil which is chromatographed (50×250 C18 Symmetrycolumn, 30-70% water: 0.1% TFA/ACN gradient) furnish the title compound(0.41 g, 1.25 mmol, 12%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H),1.73-1.94 (m, 4H), 2.00 (s, 3H), 2.24 (d, J=1.0 Hz, 3H), 2.45 (s, 3H),2.50 (s, 3H), 3.29-3.38 (m, 1H), 6.65 (s, 1H), 7.10 (s, 1H). LC/MS(m/z): calcd. for C₁₉H₂₅N₃S (M+H)⁺: 328.5. found: 328.3.

Example 121 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-4-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine

To a flask containing3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(below) (0.25 g, 0.64 mmol) and PdCl₂(dppf) (0.023 g, 0.032 mmol) isadded a solution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (2.5 mL,1.27 mmol). The solution is heated at 65° C. overnight, diluted withEtOAc (25 mL), washed with sat. NH₄Cl (20 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO (15%-20%EtOAc gradient) and is chromatographed (50×250 C18 Symmetry column,10-70% water: 0.1% TFA/ACN: 0.1% TFA gradient). The residue is dissolvedin Et₂O (20 mL), washed with sat. NaHCO₃ (15 mL) dried over MgSO₄,filtered and concentrated to furnish the title compound (0.066 g, 1.57mmol, 31%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H),2.20 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 2.61 (s, 3H), 3.29-3.38 (m,1H), 6.66 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.54(dd, J=7.5, 7.8 Hz, 1H), 7.72 (s, 1H). LC/MS (m/z): calcd. for C₂₄H₂₈N₄S(M+H)⁺: 405.2. found: 405.3.

Example 122 Preparation of3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.41 g, 1.25 mmol) and CH₂Cl₂ (30 mL) is added NBS (0.23 g, 1.32 mmol).The solution is stirred for 1 hour, diluted with Et₂O (100 mL), washedwith water (3×100 mL), brine (100 mL), dried (MgSO₄) filtered andconcentrated to furnish the title compound (0.41 g, 1.01 mmol, 80%). ¹HNMR (CDCl₃) δ 0.86 (t, J=7.4 Hz, 6H), 1.72-1.94 (m, 4H), 2.02 (s, 3H),2.18 (s, 3H), 2.43 (s, 3H), 2.49 (s, 3H), 3.27-3.36 (m, 1H), 6.67 (s,1H). LC/MS (m/z): calcd. for C₁₉H₂₄BrN₃S (M+H)⁺: 407.4. found: 407.3.

Example 123 Preparation of3-[3,4-dimethyl-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of 1-methyl-1,2,4-triazole (0.056 mL, 0.74 mmol)and THF (2 mL) is added a 1.6 M solution of n-BuLi in hexanes (0.46 mL,0.74 mmol). The solution is warmed to ambient temperature and stirredfor 30 minutes. The solution is cooled to 0° C., a 0.5 M solution ofZnCl₂ in THF (4.70 mL, 2.33 mmol) is added and the solution warmed toambient temperature and stirred for 30 minute.3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.10 g, 0.25 mmol) and PdCl₂(dppf) (0.009 g, 0.012 mmol) is added andthe solution heated at 65° C. overnight, diluted with EtOAc (25 mL),washed with sat. NH₄Cl (20 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(15%-60% EtOAc/hexane gradient), followed by a second purification byISCO column chromatography (100% Et₂O) furnish the title compound (0.07g, 0.17 mmol, 70%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.73-1.92(m, 4H), 2.06 (s, 3H), 2.29 (s, 3H), 2.47 (s, 3H), 2.51 (s, 3H),3.27-3.37 (m, 1H), 3.97 (s, 3H), 6.69 (s, 1H), 8.00 (s, 1H). LC/MS(m/z): calcd. for C₂₂H₂₈N₆S (M+H)⁺: 409.6. found: 409.2.

Example 124 Preparation of3-(3,4-dimethyl-5-thiazol-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.10 g, 0.25 mmol) and THF (1 mL) is added 1.6 M n-BuLi (0.16 mL). Thesolution is stirred for 45 minutes and 0.5 M ZnCl₂ in THF (0.52 mL, 0.26mmol) is added. The solution is warmed to ambient temperature andstirred for 30 minutes. 2-Bromo-thiazole (0.044 mL, 0.49 mmol), andPdCl₂(dppf) (0.009 g, 0.012 mmol) are added and the solution heated at65° C. overnight, diluted with EtOAc (25 mL), washed with sat. NH₄Cl (20mL), dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO column chromatography (15%-20% EtOAc/hexane gradient),furnish the title compound (6.1 mg, 0.015 mmol, 6%). ¹H NMR (CDCl₃), δ0.87 (t, J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.07 (s, 3H), 2.49 (s, 3H),2.51 (s, 3H), 2.53 (s, 3H), 3.29-3.39 (m, 1H), 6.68 (s, 1H), 7.35 (d,J=3.1 Hz, 1H), 7.86 (d, J=3.1 Hz, 1H). LC/MS (m/z): calcd. forC₂₂H₂₆N₄S₂ (M+H)⁺: 411.6. found: 411.2.

Example 125 Preparation of3-[3,4-dimethyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask containing3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.10 g, 0.25 mmol) and PdCl₂(dppf) (9 mg, 0.012 mmol) is added asolution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (0.98 mL, 0.49mmol). The solution is heated at 65° C. overnight, diluted with EtOAc(30 mL), washed with sat. NH₄Cl (30 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(15%-30% EtOAc/hexane gradient) furnish the title compound (0.029 g,0.069 mmol, 29%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.72-1.92(m, 4H), 2.04 (s, 3H), 2.45 (s, 3H), 2.47 (s, 3H), 2.50 (s, 3H), 2.59(s, 3H), 3.29-3.38 (m, 1H), 6.66 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.37(d, J=7.8 Hz, 1H), 7.60 (d, J=8.0, 7.8 Hz, 1H). LC/MS (m/z): calcd. forC₂₅H₃₀N₄S (M+H)⁺: 419.6. found: 419.4.

Example 126 Preparation of3-[3,4-dimethyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of 3-iodo-pyridine (0.15 g, 0.74 mmol) and 0.5 MZnCl₂ in THF (1.5 mL, 0.75 mmol) is added t-BuLi (0.88 mL, 1.49 mmol).The slurry is warmed to ambient temperature and stirred for 30 minutes.3-(5-bromo-3,4-dimethyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.10 g, 0.25 mmol) and Pd(PPh₃)₄ (0.014 g, 0.012 mmol) are added andthe solution stirred at ambient temperature for 2 days, diluted withEtOAc (35 mL), washed with sat. NH₄Cl (30 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO columnchromatography (20%-30% EtOAc/hexane gradient) furnish the titlecompound (6.1 mg, 0.015 mmol, 6%). ¹H NMR (CDCl₃), δ 0.88 (t, J=7.5 Hz,6H), 1.74-1.92 (m, 4H), 2.07 (s, 3H), 2.29 (s, 3H), 2.49 (s, 3H), 2.53(s, 3H), 3.30-3.39 (m, 1H), 6.68 (s, 1H), 7.36 (dd, J=8.0, 4.5 Hz, 1H),7.79-7.83 (m 1H), 8.57 (d, J=4.5 Hz, 1H), 8.79 (d, J=0.9 Hz, 1H). LC/MS(m/z): calcd. for C₂₄H₂₈N₄S (M+H)⁺: 405.6. found: 405.2.

Example 127 & 128 Preparation of8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazineand8-(1-ethyl-propyl)-3-(4-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of 3-methoxy-thiophene (2.19 g, 19.14 mmol) in Et₂O (50mL) is added 1.6 M n-BuLi (12.20 mL, 19.46 mmol). The solution is heatedat a reflux for 30 minutes and cooled to ambient temperature. Assolution of 0.5 M ZnCl₂ (38.9 mL, 19.5 mmol) and THF (50 mL) is addedand the solution is stirred for 30 minutes.8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.0 g,6.38 mmol) and PdCl₂(dppf) (0.23 g, 0.032 mmol) are added and thesolution is heated at 65° C. for 4 hours, diluted with EtOAc (250 mL),washed with sat. NH₄Cl (250 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(10%-25% EtOAc/hexane gradient) furnish the title compounds (1.50 g,4.55 mmol, 71%) and (0.23 g, 0.70 mmol, 11%), respectively.

Example 127: ¹H NMR (CDCl₃) δ 0.83 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H),2.59 (s, 3H), 2.70 (s, 3H), 3.26-3.35 (m, 1H), 3.86 (s, 3H), 6.32 (d,J=1.6 Hz, 1H), 6.67 (s, 1H), 7.41 (d, J=1.6 Hz, 1H). LC/MS (m/z): calcd.for C₁₈H₂₃N₃OS (M+H)⁺: 330.5. found: 330.3.

Example 128: ¹H NMR (CDCl₃) δ 0.84 (t, J=7.5 Hz, 6H), 1.71-1.88 (m, 4H),2.47 (s, 3H), 2.49 (s, 3H), 3.26-3.35 (m, 1H), 3.84 (s, 3H), 6.62 (s,1H), 6.96 (d, J=5.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H). LC/MS (m/z): calcd.for C₁₈H₂₃N₃OS (M+H)⁺: 330.5. found: 330.3.

Example 129 Preparation of3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.78 g, 2.37 mmol) and CH₂Cl₂ (10 mL) is added NBS (0.44 g, 2.49 mmol).The solution is stirred for 1 hour, washed with water (3×10 mL),concentrated and purified by ISCO column chromatography (5%-15%EtOAc/hexane gradient) to furnish the title compound (0.87 g, 2.13 mmol,90%). ¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46(s, 3H), 2.52 (s, 3H), 3.25-3.35 (m, 1H), 3.82 (s, 3H), 6.65 (s, 1H),6.97 (s, 1H). LC/MS (m/z): calcd. for C₁₈H₂₂BrN₃OS (M+H)⁺: 408.1. found:408.3.

Example 130 Preparation of8-(1-ethyl-propyl)-3-[3-methoxy-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask containing3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.49 mmol) and PdCl₂(dppf) (0.018 g, 0.024 mmol) is added asolution of 0.5 M 6-methyl-2-pyridylzinc bromide in THF (3.0 mL, 1.47mmol). The solution is heated at 65° C. overnight, diluted with EtOAc(30 mL), washed with sat. NH₄Cl (2×30 mL), dried over MgSO₄, filteredand concentrated. The residue is purified by ISCO column chromatography(15%-20% EtOAc/hexane gradient) furnish the title compound (0.066 g,1.57 mmol, 31%). ¹H NMR (CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m,4H), 2.50 (s, 3H), 2.51 (s, 3H), 2.55 (s, 3H), 3.26-3.37 (m, 1H), 3.90(s, 3H), 6.63 (s, 1H), 6.99 (d, J=7.4 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H),7.49 (s, 1H), 7.54 (dd, J=7.4, 7.7 Hz, 1H). LC/MS (m/z): calcd. forC₂₄H₂₈N₄OS (M+H)⁺: 421.6. found: 422.4.

Example 131 Preparation of8-(1-ethyl-propyl)-3-(3-methoxy-5-pyridin-3-yl-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of 3-iodo-pyridine (0.32 g, 1.56 mmol) and 0.5 MZnCl₂ in THF (3.20 mL, 1.59 mmol) is added t-BuLi (2.27 mL, 3.85 mmol).The solution is warmed to ambient temperature and stirred for 30minutes.3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.26 g, 0.64 mmol) and Pd(PPh₃)₄ (0.037 g, 0.032 mmol) are added andthe solution heated at 50° C. for 1 hour, cooled to ambient temperatureand stirred overnight. The solution is diluted with EtOAc (30 mL),washed with sat. NH₄Cl (2×30 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO column chromatography(20%-50% EtOAc/hexane gradient), furnish the title compound (0.16 g,0.39 mmol, 61%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m,4H), 2.52 (s, 3H), 2.55 (s, 3H), 3.28-3.38 (m, 1H), 3.93, (3H), 6.67 (s,1H), 7.26 (d, J=3.5 Hz, 1H), 7.31-7.36 (m, 1H), 7.88-7.92 (m, 1H), 8.55(d, J=4.5 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). LC/MS (m/z): calcd. forC₂₃H₂₆N₄OS (M+H)⁺: 407.6. found: 407.4.

Example 132 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-2-pyridin-4-yl-thiazol-5-yl)-imidazo[1,2-b]pyridazine,hydrochloride salt

A mixture of3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(500 mg, 1.27 mmol), 4-pyridineboronic acid (500 mg, 4 mmol), Pd(PPh₃)₄(100 mg, 0.08 mmol), toluene (2 mL), MeOH (1 mL), and K₂CO₃ (2 M aqueoussolution, 3.5 mL) is heated at 100° C. for 18 hours. Ethyl acetate (20mL) is added, and the organic layer is separated, dried over magnesiumsulfate, filtered, and concentrated in vacuo. Purification is performedvia silica gel chromatography using a 3:1 mixture of hexanes and ethylacetate to obtain the free amine of the title compound (200 mg, 40%).The purified product is dissolved in ethyl acetate and a freshlyprepared solution of hydrogen chloride (0.5 M in ethyl acetate, 2 mL) isadded. The solvent is removed in vacuo to give the title compound ¹H-NMR(CDCl₃), δ 8.2 (m, 2H); 7.05 (m, 2H); 6.55 (s, 1H); 3.24 (m, 1H); 2.43(s, 3H); 2.40 (s, 3H); 2.33 (s, 3H); 1.76 (m, 4H); 0.80 (t, 6H) ppm.MS/ES⁺=391 (100%, M+1).

Example 133 Preparation of8-(1-ethyl-propyl)-3-[3-methoxy-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 5-Bromo-1-methyl-1H-[1,2,4]triazole

To a −78° C. solution of 1-methyl-1H-[1,2,4]triazole (1.0 mL, 13.20mmol) and THF (100 mL) is added 1.6 M n-BuLi (8.70 mL, 13.86 mmol).After 45 minutes 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (1.76 mL, 14.52mmol) is added, the solution is warmed to ambient temperature andstirred for 2 hours. The solution is diluted with EtOAc (200 mL), washedwith water (150 mL), brine (150 mL), dried over MgSO₄, filtered andconcentrated to furnish the title compound (1.37 g, 8.46 mmol, 64%). ¹HNMR (CDCl₃) δ 3.82 (s, 3H), 7.78 (s, 1H). LC/MS (m/z): calcd. forC₃H₄BrN₃ (M+H)⁺: 162.0. found: 161.9.

B.8-(1-Ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-ethyl-propyl)-3-(3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.75 g, 2.28 mmol) and CH₃CN (10 mL) is added NIS (0.54 g, 2.39 mmol).The solution is stirred overnight, concentrated, diluted with EtOAc (30mL), washed with water (30 mL), sat. NH₄Cl (30 mL), 20% (NaHSO₃) (30mL), brine (30 mL), dried over MgSO₄, filtered and concentrated. Theresidue is purified by ISCO column chromatography (15%-20% EtOAc/hexanegradient) furnish the title compound (0.91 g, 2.00 mmol, 88%). ¹H NMR(CDCl₃) δ 0.85 (t, J=7.5 Hz, 6H), 1.71-1.89 (m, 4H), 2.46 (s, 3H), 2.52(s, 3H), 3.25-3.35 (m, 1H), 3.83 (s, 3H), 6.64 (s, 1H), 7.12 (s, 1H).LC/MS (m/z): calcd. for C₁₈H₂₂IN₃OS (M+H)⁺: 456.4. found: 456.0.

C. 5-Bromo-1-methyl-1H-[1,2,4]triazole

To a −78° C. solution of 1-methyl-1H-[1,2,4]triazole (1.0 mL, 13.20mmol) and THF (100 mL) is added 1.6 M n-BuLi (8.70 mL, 13.86 mmol).After 45 minutes 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (1.76 mL, 14.52mmol) is added, the solution warmed to ambient temperature and stirredfor 2 hours. The solution is diluted with EtOAc (200 mL), washed withwater (150 mL), brine (150 mL), dried over MgSO₄, filtered andconcentrated to furnish the title compound (1.37 g, 8.46 mmol, 64%). ¹HNMR (CDCl₃) δ 3.82 (s, 3H), 7.78 (s, 1H). LC/MS (m/z): calcd. forC₃H₄BrN₃ (M+H)⁺: 162.0. found: 161.9.

D.8-(1-Ethyl-propyl)-3-[3-methoxy-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a slurry of 0.05 g/mL of Reike® Zn in THF (2.8 mL, 2.11 mmol) isadded 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solutionis heated at 65° C. for 1 hour, cooled to ambient temperature and theexcess Zn allowed to settle for 1 hour. The solution is transferred to aflask containing8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.32 g, 0.70 mmol) and Pd(PPh₃)₄ (0.041 g, 0.035 mmol). The solution isheated at 65° C. overnight, diluted with EtOAc (30 mL) washed with sat.NH₄Cl (30 mL). The aqueous phase is extracted with EtOAc (20 mL). Thecombined organic layers are dried over MgSO₄, filtered and concentrated.The reside is purified by ISCO column chromatography (20%-65%EtOAc/hexane gradient) followed by ISCO column chromatography (100%Et₂O) furnish the title compound (0.19 g, 0.46 mmol, 62%). ¹H NMR(CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.51 (s, 3H), 2.52(s, 3H), 3.26-3.37 (m, 1H), 3.92 (s, 3H), 4.15 (s, 3H), 6.67 (s, 1H),7.48 (s, 1H), 7.89 (s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₆N₆OS (M+H)⁺:411.5. found: 411.3.

Example 134 Preparation of8-(1-ethyl-propyl)-3-(3-methoxy-5-thiazol-2-yl-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask containing8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.45 g, 0.99 mmol) and PdCl₂(dppf) (0.057 g, 0.078 mmol) is added a 0.5M solution of 2-thiazolylzinc bromide (9.9 mL, 4.94 mmol). The solutionis heated at 65° C. overnight, diluted with EtOAc (50 mL), washed withsat. NH₄Cl (50 mL), dried over MgSO₄, filtered and concentrated. Theresidue is purified by ISCO column chromatography (15%-20% EtOAc/hexanegradient) furnish the title compound (0.29 g, 0.70 mmol, 71%). ¹H NMR(CDCl₃) δ0.86 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.51 (s, 3H), 2.53(s, 3H), 3.28-3.37 (m, 1H), 3.93 (s, 3H), 6.67 (s, 1H), 7.28 (d, J=3.3Hz, 1H), 7.41 (s, 1H), 7.80 (d, J=3.3 Hz, 1H). LC/MS (m/z): calcd. forC₂₁H₂₄N₄OS₂ (M+H)⁺: 413.6. found: 414.3.

Example 135 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-2-morpholin-4-yl-thiazol-5-yl)-imidazo[1,2-b]pyridazine

110 mg of8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.28 mmol) and 122 mg of morpholine (1.4 mmol) are dissolved in 3.0 mlof THF and 182 mg of cesium carbonate (0.56 mmol) is added. The mixtureis put in 4 ml vial with a Teflon® lined cap and heated at 110 Covernight. The reaction mixture is concentrated and applied to asilica-gel column chromatography column with hexane:EtOAc=3:1 eluent togive 98 mg of the title compound (88%). mass spectrum (m/e): 400 (M+1);¹H-NMR (CDCl3): δ 6.70 (s, 1H), 3.87 (t, 4H, J=4.8 Hz), 3.56 (t, 4H,J=4.8 Hz), 3.35 (m, 1H) 2.56 (s, 3H), 2.46 (s, 3H), 1.86 (m, 4H), 0.90(t, 6H, J=7.6 Hz)

The following compounds are prepared essentially as described in Example135. with8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazineand the named amine:

MS (found) Ex Name Amine ¹H NMR (CDCl₃): δ (M + 1) 136.N-{5-[8-(1-Ethyl- 2M Methyl- 6.71 (s, 1H), 5.44 (s, NH), 344propyl)-2,6-dimethyl- amine/THF 3.35 (m, 1H), 3.06 (s, 3H),imidazo[1,2-b]pyridazin- 2.57 (s, 3H), 2.47 (s, 3H),3-yl]-4-methyl-thiazol-2- 2.19 (s, 3H), 1.86 (m, 4H), yl}-methylamine0.90 (t, J = 7.6 Hz, 6H). 137. N-{5-[8-(1-Ethyl- 2M 6.70 (s, 1H), 3.36(m, 1H), 358 propyl)-2,6-dimethyl- Dimethyl- 3.17 (s, 6H), 2.56 (s, 3H),imidazo[1,2-b]pyridazin- amine/THF 2.46 (s, 3H), 2.19 (s, 3H),3-yl]-4-methyl-thiazol-2- 1.85 (m, 4H), 0.90 (t, J = 7.3 Hz,yl}-dimethylamine 6H). 138. N-Ethyl-N-{5-[8-(1- N-Methyl- 6.70 (s, 1H),3.59 (q, J = 7.6 Hz, 372 ethyl-propyl)-2,6- ethylamine 2H), 3.37 (m,1H), dimethyl-imidazo[1,2- 3.15 (s, 3H), 2.57 (s, 3H), 2.48 (s,b]pyridazin-3-yl]-4- 3H), 2.19 (s, 3H), 1.85 (m, methyl-thiazol-2-yl}-4H), 1.30 (t, J = 7.5 Hz, methylamine 2H), 0.90 (t, J = 7.1 Hz, 6H).139. N-{5-[8-(1-ethyl-propyl)- Diethyl- 6.71 (s, 1H), 3.56 (q, J = 7.1Hz, 386 2,6-dimethyl- amine 4H), 3.35 (m, 1H), imidazo[1,2-b]pyridazin-2.56 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3-yl]-4-methyl-thiazol-2- 3H), 1.85(m, 4H), 1.30 (t, J = 7.3 Hz, yl}-diethylamine 6H), 0.90 (t, J = 7.3 Hz,6H). 140. N-{5-[8-(1-Ethyl- N-Methyl- 7.44 (s, 1H), 6.69 (s, 1H), 424propyl)-2,6-dimethyl- (furan-2-yl)- 6.38 (s, 2H), 4.72 (s, 2H),imidazo[1,2-b]pyridazin- methyl- 3.36 (m, 1H), 3.14 (s, 3H),3-yl]-4-methyl-thiazol-2- amine 2.57 (s, 3H), 2.48 (s, 3H),yl}-N-(furan-2- 2.20 (s, 3H), 1.85 (m, 4H), ylmethyl)-methylamine 0.90(t, J = 7.4 Hz, 6H). 141. N-{5-[8-(1-ethyl-propyl)- Thio- 6.71 (s, 1H),3.92 (m, 4H), 416 2,6-dimethyl- morpholine 3.37 (m, 1H), 2.80 (m, 4H),imidazo[1,2-b]pyridazin- 2.57 (s, 3H), 2.48 (s, 3H),3-yl]-4-methyl-thiazol-2- 2.18 (s, 3H), 1.85 (m, 4H), yl}thiomorpholine0.90 (t, J = 7.2 Hz, 6H). 142 N-{5-[8-(1-Ethyl- 2-methoxy- 6.71 (s, 1H),5.90 (s, NH), 388 propyl)-2,6-dimethyl- ethylamine 3.66 (t, J = 5.4 Hz,2H), imidazo[1,2-b]pyridazin- 3.56 (t, J = 4.6 Hz, 2H), 3.44 (s,3-yl]-4-methyl-thiazol-2- 3H), 3.35 (m, 1H), 2.57 (s,yl}-(2-methoxy-ethyl)- 3H), 2.47 (s, 3H), 2.18 (s, amine 3H), 1.85 (m,4H), 0.90 (t, J = 7.2 Hz, 6H). 143 N-{5-[8-(1-Ethyl- i-propyl- 6.69 (s,1H), 5.15 (s, NH), 372 propyl)-2,6-dimethyl- amine 3.74 (m, 1H), 3.35(m, 1H), imidazo[1,2-b]pyridazin- 2.57 (s, 3H), 2.47 (s, 3H),3-yl]-4-methyl-thiazol-2- 2.17 (s, 3H), 1.84 (m, 4H),yl}-isopropyl-amine 1.35 (d, J = 5.4 Hz, 6H), 0.90 (t, J = 7.4 Hz, 6H).144. N-{5-[8-(1-ethyl-propyl)- Pyrrolidine 6.68 (s, 1H), 3.55 (m, 4H),384 2,6-dimethyl- 3.36 (m, 1H), 2.56 (s, 3H), imidazo[1,2-b]pyridazin-2.46 (s, 3H), 2.19 (s, 3H), 3-yl]-4-methyl-thiazol-2- 2.09 (m, 4H), 1.86(m, 4H), yl}-pyrrolidine 0.91 (t, J = 7.6 Hz, 6H). 145.N-{5-[8-(1-Ethyl- n-propyl- 6.70 (s, 1H), 5.21 (s, NH), 372propyl)-2,6-dimethyl- amine 3.39 (t, J = 7.2 Hz, 2H),imidazo[1,2-b]pyridazin- 3.29 (m, 1H), 2.57 (s, 3H),3-yl]-4-methyl-thiazol-2- 2.47 (s, 3H), 2.16 (s, 3H), yl}-n-propylamine1.85 (m, 4H), 1.74 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.4Hz, 6H). 146 N-{5-[8-(1-ethyl-propyl)- Benzyl- 7.47-7.23 (m, 5H), 6.70(s, 420 2,6-dimethyl- amine 1H), 5.52 (s, NH), 6.70 (s,imidazo[1,2-b]pyridazin- 2H), 3.34 (m, 1H), 2.56 (s,3-yl]-4-methyl-thiazol-2- 3H), 2.46 (s, 3H), 2.19 (s, yl}-benzylamine3H), 1.85 (m, 4H), 0.91 (t, J = 7.2 Hz, 6H). 147N-{5-[8-(1-ethyl-propyl)- N-(2- 416 2,6-dimethyl- Methoxy-imidazo[1,2-b]pyridazin- ethyl)- 3-yl]-4-methyl-thiazol-2- ethylamineyl}-N-(2-methoxy-ethyl)- ethylamine 148 N-{5-[8-(1-Ethyl-N-(2-methoxyethyl)- 6.69 (s, 1H), 3.72 (m, 4H), 430propyl)-2,6-dimethyl- n- 3.47 (t, J = 7.4 Hz, 2H),imidazo[1,2-b]pyridazin- propyl- 3.42 (s, 3H), 3.36 (m, 1H),3-yl]-4-methyl-thiazol-2- amine 2.57 (s, 3H), 2.47 (s, 3H), 2.16 (s,yl}-(2-methoxy-ethyl)-n- 3H), 1.87 (m, 6H), 0.99 (t, J = 7.2 Hz,propylamine 3H), 0.91 (t, J = 7.5 Hz, 6H). 149 N-{5-[8-(1-ethyl-propyl)-piperidine 6.68 (s, 1H), 3.53 (t, J = 4.7 Hz, 398 2,6-dimethyl- 4H),3.36 (m, 1H), imidazo[1,2-b]pyridazin- 2.56 (s, 3H), 2.46 (s, 3H), 2.17(s, 3-yl]-4-methyl-thiazol-2- 3H), 1.86 (m, 4H), 1.71 (m, yl}-piperidine6H), 0.90 (t, J = 7.4 Hz, 6H). 150 N-{5-[8-(1-ethyl-propyl)- 3-amino-6.70 (s, 1H), 5.24 (s, NH), 400 2,6-dimethyl- pentane 3.32 (m, 2H), 2.57(s, 3H), imidazo[1,2-b]pyridazin- 2.47 (s, 3H), 1.94 (s, 3H),3-yl]-4-methyl-thiazol-2- 1.85 (m, 4H), 1.72 (m, 2H), yl}-3-pentylamine1.60 (m, 2H), 1.02 (t, J = 7.5 Hz, 6H), 0.90 (t, J = 7.3 Hz, 6H). 151N-{5-[8-(1-ethyl-propyl)- Cyclo- 6.70 (s, 1H), 6.51 (s, NH), 3702,6-dimethyl- propylamine 3.35 (m, 1H), 2.67 (m, 1H),imidazo[1,2-b]pyridazin- 2.57 (s, 3H), 2.47 (s, 3H),3-yl]-4-methyl-thiazol-2- 2.18 (s, 3H), 1.85 (m, 4H),yl}-cyclo-propylamine 0.91 (t, J = 7.3 Hz, 6H), 0.82 (m, 2H), 0.77 (m,2H). 152 N-{5-[8-(1-ethyl-propyl)- Allylamine 6.70 (s, 1H), 6.0 (m, 1H),370 2,6-dimethyl- 5.60 (s, NH), 5.38 (dd, J = 1.3,imidazo[1,2-b]pyridazin- 17.4 Hz, 1H), 5.27 (dd,3-yl]-4-methyl-thiazol-2- J = 1.2, 10.3 Hz, 1H), 4.0 (d, yl}-allylamineJ = 5.2 Hz, 2H), 3.45 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.17 (s, 3H),1.85 (m, 4H), 0.91 (t, J = 6.8 Hz, 6H). 153 N-{5-[8-(1-ethyl-propyl)-1,2,3,6-tetra- 6.70 (s, 1H), 5.96 (m, 1H), 396 2,6-dimethyl- hydro- 5.81(m, 1H), 4.02 (t, J = 3.1 Hz, imidazo[1,2-b]pyridazin- pyridine 2H),3.72 (t, J = 5.5 Hz, 3-yl]-4-methyl-thiazol-2- 2H), 3.35 (m, 1H), 2.57(s, yl}-1,2,3,6-tetra-hydro- 3H), 2.47 (s, 3H), 2.35 (m, pyridine 2H),2.19 (s, 3H), 1.87 (m, 4H), 0.90 (t, J = 7.4 Hz, 6H). 154N-Ethyl-N-{5-[8-(1- N-ethyl-n- 6.69 (s, 1H), 3.58 (q, J = 7.1 Hz, 400ethyl-propyl)-2,6- propyl- 2H), 3.43 (t, J = 7.5 Hz,dimethyl-imidazo[1,2- amine 2H), 3.36 (m, 1H), 2.57 (s,b]pyridazin-3-yl]-4- 3H), 2.47 (s, 3H), 2.18 (s, methyl-thiazol-2-yl}-n-3H), 1.80 (m, 4H), 1.30 (t, J = 6.9 Hz, propylamine 3H), 1.04 (t, J =6.9 Hz, 3H), 0.91 (t, J = 7.5 Hz, 6H). 155 N-Methyl-N-{5-[8-(1-N-methyl-n- 6.68 (s, 1H), 3.46 (t, J = 8.3 Hz, 386 Ethyl-propyl)-2,6-propyl- 2H), 3.35 (m, 1H), dimethyl-imidazo[1,2- amine 3.16 (s, 3H),2.56 (s, 3H), 2.46 (s, b]pyridazin-3-yl]-4- 3H), 2.17 (s, 3H), 1.80 (m,methyl-thiazol-2-yl}-n- 2H), 1.00 (t, J = 7.7 Hz, propylamine 3H), 0.91(t, J = 7.1 Hz, 6H). 156 N-Methyl-N-{5-[8-(1- N-Methyl-2- 6.70 (s, 1H),4.40 (m, 1H), 386 Ethyl-propyl)-2,6- propyl- 3.36 (m, 1H), 2.99 (s, 3H),dimethyl-imidazo[1,2- amine 2.57 (s, 3H), 2.46 (s, 3H),b]pyridazin-3-yl]-4- 2.18 (s, 3H), 1.85 (m, 4H), methyl-thiazol-2-yl}-1.29 (d, J = 6.4 Hz, 6H), isopropyl-amine 0.90 (t, J = 7.1 Hz, 6H). 157N-Methyl-N-{5-[8-(1- N-Methyl-2- 6.70 (s, 1H), 4.40 (d, J = 2.5 Hz, 382Ethyl-propyl)-2,6- Propyn-1- 2H), 3.35 (m, 1H), dimethyl-imidazo[1,2-amine 3.17 (s, 3H), 2.56 (s, 3H), 2.45 (s, b]pyridazin-3-yl]-4- 3H),2.34 (m, 1H), 2.19 (s, methyl-thiazol-2-yl}-2- 3H), 1.85 (m, 4H), 0.90(t, J = 7.1 Hz, propyn-1-amine 6H). 158 N-Methyl-N-{5-[8-(1- N-Methyl-3-6.71 (s, 1H), 3.92 (t, J = 6.4 Hz, 397 ethyl-propyl)-2,6- amino- 2H),3.37 (m, 1H), dimethyl-imidazo[1,2- propionitrile 3.25 (s, 3H), 2.9 (t,J = 6.4 Hz, b]pyridazin-3-yl]-4- 2H), 2.58 (s, 3H), 2.48 (s,methyl-thiazol-2-yl}-3- 3H), 2.18 (s, 3H), 1.86 (m, amino-propionitrile4H), 0.91 (t, J = 7.4 Hz, 6H). 159 N-{5-[8-(1-ethyl-propyl)- Cyclo- 6.68(s, 1H), 5.35 (s, NH), 384 2,6-dimethyl- propyl- 3.34 (m, 1H), 3.19 (t,J = 6.3 Hz, imidazo[1,2-b]pyridazin- methyl- 2H), 2.56 (s, 3H),3-yl]-4-methyl-thiazol-2- amine 2.45 (s, 3H), 2.16 (s, 3H),yl}-cyclopropyl- 1.86 (m, 4H), 1.19 (m, 1H), methylamine 0.91 (t, J =7.1 Hz, 6H), 0.61 (m, 2H), 0.31 (m, 2H). 160 N-{5-[8-(1-Ethyl- 2-methyl-6.72 (s, 1H), 5.58 (s, NH), 404 propyl)-2,6-dimethyl- sulfanyl- 3.58 (m,2H), 3.35 (m, J = 7.3, imidazo[1,2-b]pyridazin- ethylamine 14.4, 1H),2.85 (m, 2H), 3-yl]-4-methyl-thiazol-2- 2.57 (s, 3H), 2.46 (s, 3H),yl}-(2-methylsulfanyl)- 2.17 (s, 6H), 1.85 (m, 4H), ethylamine 0.90 (t,J = 6.7 Hz, 6H). 161 N-{5-[8-(1-Ethyl- N-{[1,3]dioxolan- 6.72 (s, 1H),5.22 (m, 1H), 430 propyl)-2,6-dimethyl- 2-yl- 4.05 (m, 2H), 3.94 (m,2H), imidazo[1,2-b]pyridazin- methyl}- 3.73 (d, J = 4.5 Hz, 2H),3-yl]-4-methyl-thiazol-2- methyl- 3.35 (m, J = 6.6, 14.1 Hz,yl}-N-{[1,3]dioxolan-2- amine 1H), 3.23 (s, 3H), 2.56 (s,ylmethyl-methylamine 3H), 2.46 (s, 3H), 2.17 (s, 3H), 1.84 (m, 4H), 0.91(t, J = 7.1 Hz, 6H). 162 N-{5-[8-(1-ethyl-propyl)- N-Methyl-2- 6.71 (s,1H), 5.93 (m, 2H), 384 2,6-dimethyl- propen-1-yl- 5.30 (m, 2H), 4.16 (d,J = 5.9 Hz, imidazo[1,2-b]pyridazin- amine 2H), 3.39 (m, 1H),3-yl]-4-methyl-thiazol-2- 3.12 (s, 3H), 2.58 (s, 3H),yl}-N-Methyl-2-propen- 2.48 (s, 3H), 2.20 (s, 3H), 1-yl-amine 1.86 (m,4H), 0.91 (t, J = 7.5 Hz, 6H). 163 (R)—N-{5-[8-(1-Ethyl- (R)- 6.70 (s,1H), 5.44 (s, NH), 414 propyl)-2,6-dimethyl- (tetrahydro- 4.20 (m, 1H),3.94 (m, 1H), imidazo[1,2-b]pyridazin- furan-2- 3.84 (m, 1H), 3.60 (m,1H), 3-yl]-4-methyl-thiazol-2- ylmethyl)- 3.35 (m, 1H), 2.57 (s, 3H),yl}-(tetrahydro-furan-2- amine 2.47 (s, 3H), 2.18 (s, 3H),ylmethyl)-amine 2.08 (m, 1H), 1.98 (m, 2H), 1.85 (m, 4H), 1.73 (m, 2H),0.90 (t, J = 7.3 Hz, 6H). 164 (S)—N-{5-[8-(1-Ethyl- (S)- 6.69 (s, 1H),5.45 (s, NH), 414 propyl)-2,6-dimethyl- (tetrahydro- 4.20 (m, 1H), 3.94(m, 1H), imidazo[1,2-b]pyridazin- furan-2- 3.84 (m, 1H), 3.59 (m, 1H),3-yl]-4-methyl-thiazol-2- ylmethyl)- 3.34 (m, 2H), 2.57 (s, 3H),yl}-(tetrahydro-furan-2- amine 2.47 (s, 3H), 2.17 (s, 3H),ylmethyl)-amine 2.08 (m, 1H), 1.98 (m, 2H), 1.85 (m, 4H), 1.73 (m, 1H),0.90 (t, J = 7.2 Hz, 6H). 165 N-{5-[8-(1-Ethyl- N-Methyl-2- 6.70 (s,1H), 3.74 (t, J = 4.2 Hz, 402 propyl)-2,6-dimethyl- methoxy- 2H), 3.71(t, J = 4.1 Hz, imidazo[1,2-b]pyridazin- ethyl-amine 2H), 3.43 (s, 3H),3.37 (m, 3-yl]-4-methyl-thiazol-2- 1H), 3.22 (s, 3H), 2.57 (s,yl}-N-(2-methoxyethyl)- 3H), 2.47 (s, 3H), 2.18 (s, methylamine 3H),1.85 (m, 4H), 0.90 (t, J = 7.1 Hz, 6H). 166 N-{5-[8-(1-ethyl-propyl)-N-Methyl- 7.43-7.32 (m, 5H), 6.69 (s, 434 2,6-dimethyl- benzyl- 1H),4.76 (s, 2H), 3.35 (m, imidazo[1,2-b]pyridazin- amine 1H), 3.10 (s, 3H),2.57 (s, 3-yl]-4-methyl-thiazol-2- 3H), 2.48 (s, 3H), 2.21 (s,yl}-N-methyl- 3H), 1.85 (m, 4H), 0.91 (t, J = 7.3 Hz, benzylamine 6H).167 N-{5-[8-(1-ethyl-propyl)- N-Ethyl- 7.41-7.31 (m, 5H), 6.68 (s, 4482,6-dimethyl- benzyl- 1H), 4.76 (s, 2H), 3.54 (q, J = 7.3,imidazo[1,2-b]pyridazin- amine 2H), 3.36 (m, 1H),3-yl]-4-methyl-thiazol-2- 2.56 (s, 3H), 2.49 (s, 3H),yl}-N-ethyl-benzylamine 2.20 (s, 3H), 1.85 (m, 4H), 1.26 (t, J = 7.2 Hz,3H), 0.91 (t, J = 7.1 Hz, 6H). 168 N-{5-[8-(1-Ethyl- 1-Methoxy- 416propyl)-2,6-dimethyl- 2-amino- imidazo[1,2-b]pyridazin- butane3-yl]-4-methyl-thiazol-2- yl}-(1-methoxy-2-butyl)- amine 169N-{5-[8-(1-Ethyl- N,2-Di- 400 propyl)-2,6-dimethyl- methyl-n-imidazo[1,2-b]pyridazin- propyl- 3-yl]-4-methyl-thiazol-2- amineyl}-N-methyl- isobutylamine 170 N-{5-[8-(1-Ethyl- 2-Methyl-n- 386propyl)-2,6-dimethyl- propyl- imidazo[1,2-b]pyridazin- amine3-yl]-4-methyl-thiazol-2- yl}-isobutyl-amine

Example 171 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(1-methyl-¹H-pyrrol-2-yl)-imidazo[1,2-b]pyridazine

A THF solution (10 mL) of N-methylpyrrole (Aldrich, 800 μL, 9.0 mmol) iscooled to −78° C. under N₂ then treated with tert-BuLi (1.7 M inpentane, 5.3 mL, 9.0 mmol). The solution is warmed to room temperaturefor 30 minutes then cooled to −78° C. and treated with ZnCl₂ (Aldrich,0.5 M in THF, 18 mL, 9.0 mmol). The resulting mixture is warmed to roomtemperature and treated with a THF slurry (5 mL) containing8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.02gm, 3.0 mmol) and PdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 140 mg, 0.17mmol). The mixture is heated to 60° C. overnight, then poured into sat'daq NH₄Cl (50 mL) and extracted with diethyl ether (75 mL). The organicextract is ished with aq. brine, dried over Na₂SO₄, filtered, andconcentrated. The crude product is purified by chromatography usinghexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate inhexane) to elute the title compound (407.5 mg, 46% yield) as an oil.

ES-MS (m/z): calc'd for C₁₈H₂₄N₄: 296.20. found 297.5 (M+H)⁺

¹H NMR (400 mHz, CDCl₃): δ 6.86 (s, 1H), 6.65 (s, 1H), 6.32-6.28 (m,2H), 3.50 (s, 3H), 3.35 (br s, 1H), 2.49 (s, 3H), 2.46 (s, 3H),1.87-1.75 (m, 4H), 0.87 (t, J=7.0 Hz, 6H).

Example 172 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[1-methyl-5-(3-methyl-thiophen-2-yl)-¹H-pyrrol-2-yl]-imidazo[1,2-b]pyridazine

A.3-(5-Bromo-1-methyl-¹H-pyrrol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A THF solution (10 mL) of8-(1-ethyl-propyl)-2,6-dimethyl-3-(1-methyl-1H-pyrrol-2-yl)-imidazo[1,2-b]pyridazine(414 mg, 1.40 mmol) is cooled to 0° C. and treated with a THF solutionof NBS (250 mg, 1.40 mmol). Within 5 min, the reaction mixture istreated with sat Na₂SO₃ (1 mL) then concentrated. The resulting residueis diluted with ethyl acetate (50 mL) and ished with 50% aq sat'd Na₂SO₃(2×50 mL). The organic extract is dried over Na₂SO₄, filtered, andconcentrated. The crude product is purified by chromatography usinghexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate inhexane) to elute the title compound (374 mg, 71% yield) as a solid.ES-MS (m/z): calc'd for C₁₈H₂₃BrN₄: 374.11. found 375 (M+H)⁺. ¹H NMR(400 mHz, CDCl₃): δ 6.67 (s, 1H), 6.33 (d, J=4.0 Hz, 1H), 6.30 (d, J=4.0Hz, 1H), 3.40 (s, 3H), 3.36 (br s, 1H), 2.50 (s, 3H), 2.44 (s, 3H),1.88-1.75 (m, 4H), 0.87 (t, J=7.3 Hz, 6H).

B.8-(1-Ethyl-propyl)-2,6-dimethyl-3-[1-methyl-5-(3-methyl-thiophen-2-yl)-¹H-pyrrol-2-yl]-imidazo[1,2-b]pyridazine

A THF slurry (5 mL) of3-(5-bromo-1-methyl-¹H-pyrrol-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(143 mg, 0.38 mmol) and PdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 19 mg,0.023 mmol) is treated with 3-methyl-2-thienyl zinc bromide (Aldrich,0.5 M in THF, 3.8 mL, 1.9 mmol) then heated to 60° C. for 1 hr. Theresulting mixture is poured into sat'd NH₄Cl (25 mL) and extracted withdiethyl ether (35 mL). The organic extract is washed with aq. NaCl,dried over Na₂SO₄, filtered, and concentrated. The crude product ispurified by chromatography using hexane-ethyl acetate gradient (100%hexane to 15% ethyl acetate in hexane) to elute the product. Thematerial is purified a second time by flash chromatography usinghexane-ethyl acetate gradient (100% hexane to 12% ethyl acetate inhexane) to elute the product. Only the fractions containing pure desiredproduct, as judged by MS analysis, are collected and give the titlecompound (82.6 mg, 55% yield) as an oil. ES-MS (m/z): calc'd forC₂₃H₂₈N₄S: 392.20. found 393.1 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃): δ 7.28(d, J=5.3 Hz, 1H), 6.96 (d, J=4.8 Hz, 1H), 6.67 (br s, 1H), 6.39 (d,J=3.5 Hz, 1H), 6.37 (d, J=4.0 Hz, 1H), 3.35 (br s, 1H), 3.33, (s, 3H),2.52 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H), 1.89-1.76 (m, 4H), 0.87 (t,J=7.5 Hz, 6H).

Example 173 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-ylamine

50 mg of8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.13 mmol) and 10 mg of copper (I) oxide are added to 3 ml of 2 M NH3in MeOH and vial is capped with a Teflon® lined cap, heated at 130° C.for overnight. The reaction mixture is concentrated under N2 gas andapplied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 inMeOH=20:20:1) to give 22 mg of the title compound. Yield 54%: massspectrum (m/e): 330 (M+1); ¹H-NMR (CDCl3): 6.72 (s, 1H), 5.24 (br, 2H),3.40 (m, 1H), 2.56 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.85 (m, 4H),0.90 (t, 6H, J=7.4 Hz).

Example 174 Preparation ofN-{5-[7-bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine

A.7-Bromo-3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

547 mg of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-methyl-thiazol-5-yl)-imidazo[1,2-b]pyridazine(1.74 mmol) and 341 mg of NBS (1.92 mmol) are dissolved in 20 ml ofCHCl3 and stirred at room temperature overnight. The reaction mixture iswashed with sat. Na₂S₂O₃, sat. NaCl, dried over Na₂SO₄ and evaporated.The crude materials are applied onto a silica-gel chromatography column(Hexane:AcOEt=8:1) to give 218 mg of the title compound. Yield 27%. massspectrum (m/e): 473 (M+1); ¹H-NMR (CDCl3): 3.44 (m, 1H), 2.70 (s, 3H),2.45 (s, 3H), 2.37 (s, 3H), 2.03 (m, 4H), 0.90 (m, 6H).

B.N-{5-[7-bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine

72 mg of7-bromo-3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.15 mmol) and 66 mg of morpholine (0.76 mmol) and 97 mg of cesiumcarbonate (0.3 mmol) are put in 4 ml vial with 3 ml of dry THF. The vialis capped with a Teflon® lined cap and heated at 100° C. overnight. Thereaction mixture is concentrated and applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1) to give 30 mg of the titlecompound. Yield 42%: mass spectrum (m/e): 479 (M+1); ¹H-NMR (CDCl3):3.87 (t, 4H, J=5.0 Hz), 3.55 (t, 4H, J=5.0 Hz), 3.45 (m, 1H), 2.70 (s,3H), 2.44 (s, 3H), 2.40 (m, 2H), 2.18 (s, 3H), 2.01 (m, 2H), 0.88 (t,6H, J=7.3 Hz).

Example 175 Preparation of3-[3-chloro-4-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine,hydrochloride salt

Reike® Zn (0.5 g/mL solution in THF (1.9 mL, 1.45 mmol) is added to aflask containing3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.73 mmol). The slurry is heated at 65° C. for 1 hour, placedin a centrifuge for 5 minutes, and the resulting solution is transferredto a flask containing 2-bromo-6-methyl-pyridine (0.12 g, 0.73 mmol) andPdCl₂(dppf) (0.018 g, 0.024 mmol). The reaction is heated at 65° C.overnight, diluted with ethyl acetate (20 mL), and washed with a sat.solution of NH₄Cl (15 mL). The organic layer is dried over MgSO₄,filtered, and concentrated. The residue is purified by silica gelchromatography using a hexanes and ethyl acetate gradient. The resultingproduct is dissolved in dichloromethane (5 mL), treated with a 1 Msolution of HCl in EtOH (0.35 mL, 0.35 mmol) and concentrated. Theresidue is recrystallized from ethyl acetate and hexanes furnish thetitle compound (0.033 g, 0.072 mmol, 11%). ¹H-NMR (CDCl₃), δ 0.95 (t,J=7.3 Hz, 6H), 1.73-2.02 (m, 4H), 2.68 (s, 3H), 2.81 (s, 3H), 3.21 (s,3H), 3.88-3.98 (m, 1H), 7.25 (s, 1H), 7.65 (d, J=7.5 Hz, 1H), 8.09 (d,J=7.5 Hz, 1H), 8.33 (dd, J=7.5, 7.1 Hz, 1H), 9.26 (s, 1H) ppm. LC/MS(m/z): calcd. for C₂₃H₂₆Cl₂N₄S (M+H)⁺: 424.2. found: 424.2.

Example 176 Preparation of3-(3-chloro-4-pyridin-3-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine,hydrochloride salt

Using a procedure analogous to Example 175,3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 0.97 mmol), Reike® Zn (0.5 g/mL solution in THF, 2.5 mL, 1.94mmol), 3-iodo-pyridine (0.30 g, 1.45 mmol), PdCl₂(dppf) (0.035 g, 0.048mmol), and a 1 M solution of HCl in EtOH (0.61 mL, 0.61 mmol) furnishthe title compound (0.076 g, 0.17 mmol, 18%). ¹H-NMR (CDCl₃), δ 0.95 (t,J=7.0 Hz, 6H), 1.71-1.88 (m, 2H), 1.88-2.01 (m, 2H), 2.68 (s, 3H), 2.81(s, 3H), 3.85-3.96 (m, 1H), 5.28 (s, 1H), 7.27 (bs, 1H), 8.09 (bs, 1H),8.23 (bs, 1H), 8.70 (bs, 1H), 8.89 (bs, 1H), 9.18 (bs, 1H). LC/MS (m/z):calcd. for C₂₂H₂₄Cl₂N₄S (M+H)⁺: 411.1. found: 411.2.

Example 177 Preparation of3-(3-chloro-4-thiazol-2-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 175,3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.61 mmol), Reike® Zn (0.5 μl mL solution in THF, 1.6 mL, 1.21mmol), 2-bromo-thiazole (0.11 mL, 1.21 mmol), and PdCl₂(dppf) (0.022 g,0.030 mmol) furnish the title compound (0.012 g, 0.29 mmol, 6.8%).¹H-NMR (CDCl₃), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.52 (s,6H), 3.27-3.43 (m, 1H), 6.73 (s, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.94 (d,J=3.3 Hz, 1H), 8.30 (s, 1H) ppm. LC/MS (m/z): calcd. for C₂₀H₂₁ClN₄S₂(M+H)⁺: 417.1. found: 417.2.

Example 178 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-N-methyl-acetamide

60 mg ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine(0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0ml of CH₂Cl₂ and 16 mg of acetylchloride (0.2 mmol) is added. The vialis capped with a Teflon® lined cap and shaken at room temperature for 2h. The reaction mixture is concentrated and applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1 and Hexane:AcOEt=2:1) to give33.8 mg of the title compound. Yield 50%: mass spectrum (m/e): 386(M+1); ¹H-NMR (CDCl3): 7.03 (s, 1H), 3.79 (s, 3H), 3.47 (m, 1H), 2.54(s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 1.86 (m, 4H), 0.91(t, 6H, J=7.4 Hz).

Example 179 Preparation ofN-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-N-methanesulfonyl-methylamine

60 mg ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine(0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0ml of CH₂Cl₂ and 23 mg of methanesulfonyl chloride (0.2 mmol) is added.The vial is capped with a Teflon® lined cap and shaken at roomtemperature for 2 h. The reaction mixture is concentrated and applied tosilica-gel chromatography (Hexane:AcOEt=2:1) to give 53.8 mg of thetitle compound. Yield 75%. mass spectrum (m/e): 422 (M+1); ¹H-NMR(CDCl3): 6.96 (s, 1H), 3.60 (s, 3H), 3.34 (m, 1H), 3.19 (s, 3H), 2.56(s, 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.4Hz).

Example 180 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-N-ethanesulfonyl-methylamine

The title compound is prepared by a procedure analogous to Example 178.employing 50 mg ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine(0.15 mmol), 51 mg of triethylamine (0.5 mmol) and 39 mg ofethanesulfonylchloride (0.3 mmol). 48.9 mg, Yield 75%: mass spectrum(m/e): 436 (M+1); ¹H-NMR (CDCl3): 6.73 (s, 1H), 3.62 (s, 3H), 3.42 (q,2H, J=7.4 Hz), 3.35 (m, 1H), 2.55 (s, 3H), 2.48 (s, 3H), 2.28 (s, 3H),1.85 (m, 4H), 1.46 (t, 3H, J=7.4 Hz), 0.90 (t, 6H, J=7.5 Hz).

Example 181 Preparation of3-[2-(1,1-dioxo-thiomorpholin-4-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

60 mg ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}thiomorpholine(0.14 mmol) is dissolved in 3 ml of CH₂Cl₂ and 62 mg of mCPBA (0.36mmol) is added. The reaction mixture is stirred at room temperature for30 min. The reaction mixture is diluted with CH₂Cl₂, washed with sat.NaHCO3 and sat. NaCl. The separated organic layer is dried over Na₂SO₄and evaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 20.3mg of the title compound. Yield 33%: mass spectrum (m/e): 448 (M+1).¹H-NMR: 6.72 (s, 1H), 4.16 (t, J=4.7 Hz, 4H), 3.35 (m, 1H), 3.23 (t,J=5.2 Hz, 4H), 2.57 (s, 3H), 2.48 (s, 3H), 2.19 (s, 3H), 1.86 (m, 4H),0.90 (t, J=7.1 Hz, 6H).

Example 182 Preparation of3-[2-(3,5-Dimethyl-pyrazol-1-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A.{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-hydrazine

The title compound is prepared essentially as described in Example 135using hydrazine. MS found (M+1) 345.

B.3-[2-(3,5-Dimethyl-pyrazol-1-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

28 mg of{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-hydrazine(0.08 mmol) and 80 mg of 2,4-pentanedione (0.8 mmol) are dissolved in1.0 ml of AcOH and heated at 100° C. for 2 h. The reaction mixture isconcentrated and applied onto a silica-gel chromatography column(Hexane:AcOEt=5:1) to give 23 mg of the title compound. Yield 70%: massspectrum (m/e): 409 (M+1). 6.72 (s, 1H), 6.03 (s, 1H), 3.36 (m, J=7.1,14.1 Hz, 1H), 2.75 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H),2.31 (s, 3H), 1.87 (m, 4H), 0.91 (t, J=7.5 Hz, 6H).

Example 183 Preparation of3-(3-chloro-4-pyridin-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine,hydrochloride salt

A solution of3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 g, 0.61 mmol), 4-pyridyl-boronic acid (0.82, 0.67 mmol), a 2 Msolution of Na₂CO₃ (0.5 mL, 0.91 mmol), and n-PrOH (2.5 mL) are degassedwith nitrogen for 10 minutes. Pd(OAc)₂ (0.0027 g, 0.012 mmol) and PPh₃(0.0095 g, 0.036 mmol) are added, and the solution heated at a 90° C.overnight. The solution is diluted with ethyl acetate (40 mL) and washedwith a 10% solution of Na₂CO₃ (30 mL). The organic layer is dried overMgSO₄, filtered, and concentrated. The residue is purified by ISCO flashchromatography (20%-30% EtOAc gradient). The resulting product isdissolved in dichloromethane (5 mL), treated with a 1 M solution of HClin EtOH (0.35 mL, 0.35 mmol), and concentrated. The residue isrecrystallized from acetonitrile and ethyl acetate furnish the titlecompound (0.15 g, 0.34 mmol, 56%). 1H-NMR (CDCl₃), δ 0.95 (t, J=7.5 Hz,6H), 1.73-1.88 (m, 2H), 1.89-2.04 (m, 2H), 2.68 (s, 3H), 2.82 (s, 3H),3.87-3.97 (m, 1H), 7.28 (s, 1H), 8.26-8.34 (m, 3H), 8.95 (d, J=5.3 Hz,2H) ppm. LC/MS (m/z): calcd. for C₂₂H₂₄Cl₂N₄S (M+H)⁺: 411.1. found:411.2.

Example 184 Preparation of3-[2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A.4-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-tetrahydro-pyran-4-ol

370 mg of3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.93 mmol) is dissolved in 10 ml of dry THF and cooled to −78° C. 0.6ml of n-BuLi 2.0 M in hexane (1.2 mmol) is added and stirred at −78° C.for 30 min. 141 mg of tetrahydro-4H-pyran-4-one (1.41 mmol) is added andstirred at −78° C. for 2 h. The reaction mixture is diluted with AcOEt,washed with sat. NH4Cl, dried over Na2SO4 and evaporated. The crudeproduct is applied onto a silica-gel chromatography column(Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 152 mg of the titlecompound. Yield 40%: mass spectrum (m/e): 415 (M+1). ¹H NMR (CDCl₃): δ6.74 (s, 1H), 3.99 (t, J=2.2 Hz, 4H), 3.97 (t, J=2.2 Hz, 4H), 3.35 (m,1H), 3.20 (s, OH), 2.56 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 1.88 (m,4H), 0.91 (t, J=7.3 Hz, 6H).

B.3-[2-(3,6-Dihydro-2H-pyran-4-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

150 mg of4-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-tetrahydro-pyran-4-ol(0.36 mmol) is dissolved in 5 ml of CH2Cl2 and 112 mg of triethylsilane(0.96 mmol) and 717 mg of trifluoroacetic acid (6.3 mmol) are added. Thereaction mixture is stirred at room temperature for 1 h. The reactionmixture is stirred under reflux for 1 h and cooled down to roomtemperature. The solvent is removed in vacuo. The crude product isapplied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 inMeOH=10:3:1) to give 64 mg of the title compound. Yield 45%. massspectrum (m/e): 397 (M+1). 6.94 (s, 1H), 6.71 (s, 1H), 4.41 (d, J=2.6Hz, 2H), 3.98 (t, J=5.3 Hz, 2H), 3.43 (m, 1H), 2.62 (s, 3H), 2.75 (m,2H), 2.56 (s, 3H), 2.37 (s, 3H), 1.86 (m, 4H), 0.92 (t, J=8.2 Hz, 6H).

Example 185 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[4-methyl-2-(tetrahydro-pyran-4-yl)-thiazol-5-yl]-imidazo[1,2-b]pyridazine

Add3-[2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(55 mg, 0.14 mmol), 5% palladium on carbon (55 mg) and absolute ethanol(50 ml) to a pressure vessel. Purge the reaction vessel with nitrogen,purge the reaction vessel with hydrogen, pressurize the reaction mixturewith hydrogen (415 KPa), seal the vessel, agitate the reaction and heatto 40° C. Continue the reaction for 18 hours then turn off the heat andallow the reaction mixture to cool to ambient temperature. Vent theexcess hydrogen from the vessel and purge the vessel with nitrogen.Filter the reaction mixture to remove the 5% palladium on carbon. Thefiltrate is concentrated and applied onto a silica-gel chromatographycolumn (Hexane:AcOEt:2 M NH₃ in MeOH=10:3:1) to give 12.8 mg of thetitle compound. Yield 23%. mass spectrum (m/e): 399 (M+1). ¹H NMR(CDCl₃): δ 6.73 (s, 1H), 4.14 (m, 2H), 3.60 (m, 2H), 3.34 (m, 2H), 2.56(s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.16 (m, 2H), 2.02 (m, 2H), 1.87(m, 4H), 0.91 (t, J=7.6 Hz, 6H).

Example 186 Preparation of3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine

A. 6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine

6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine can be made usingchemistry described in J. Heterocylic Chem. 1991, 28, 583. A 250 mLthree neck round bottom flask is charged with 3-amino-6-methylpyridazine(2.5 g, 0.229 moles, 1.0 equiv), water (70 mL), and acetonitrile (50mL). Concentrated sulfuric acid (3.51 g, 1.91 mL, 0.0344 moles, 1.5equiv), silver nitrate (3.87 g, 0.0229 moles, 1.0 equiv), and valproicacid (7.21 g, 7.95 mL, 0.050 moles, 2.2 equiv) are added to the reactionmixture. The reaction is heated to 75° C. As the reaction mixture isheating, a solution of (NH₄)₂S₂O₈ (7.85 g, 0.0344 moles, 1.5 equiv) in40 mL of water is slowly added via an addition funnel over a period of30 minutes. The reaction mixture is heated at 70-80° C. for two morehours. The reaction mixture is cooled and dichloromethane is added. Thereaction is made basic with a 30% aqueous NaOH solution and filteredthrough a short Celite® plug. The organic layer is separated, and theaqueous layer is extracted two more times with dichloromethane. Thecombined organic extracts are dried over Na₂SO₄. The solvent isevaporated and the crude material is purified using silica gelchromatography with a 2.0 N solution of NH₃ in MeOH and methylenechloride as eluent. Yield=0.61 g (13%). MS (APCI): 208 (M+1).

B. 2,6-Dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine

A 250 mL round bottom flask is charged with6-methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine (0.611 g, 0.00295 moles,1 equiv), ethanol 2B (30 mL), and chloroacetone (0.382 g, 0.328 ml,0.00412 moles, 1.4 equiv). The reaction mixture is heated at 75° C.overnight and then cooled to room temp. NaHCO₃ (0.371 g, 0.00442 moles,1.5 equiv) is slowly added to the reaction mixture that is then heatedto 100° C. overnight. The reaction mixture is cooled and the solvent isevaporated. Dichloromethane is added and the reaction mixture is passedthrough filter paper. The solvent is evaporated to obtain a brown oilwhich is purified via silica gel chromatography. The material is elutedwith a hexanes and ethyl acetate gradient to obtain 0.511 g of the finalproducts. Two peaks are identified in the lc/ms. The mixture is used “asis” in the next reaction. MS (APCI): 246 (M+1). sC.3-Iodo-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine

A 50 mL round bottom flask is charged with2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (0.51 g, 0.0021moles) and acetonitrile (3 mL). The reaction mixture is placed on an icebath and NIS (0.468 g, 0.00208 moles) is added neat. The reaction isstirred overnight and the ice bath melts. The next day, the reactionmixture is partitioned between dichloromethane and a saturated aqueoussolution of NaHCO₃. The organic layer is collected and the aqueous layeris extracted two more times with dichloromethane. The organic extractsare combined, washed with brine, and dried over Na₂SO₄. The solvent isevaporated and the crude material is purified via silica gelchromatography eluting with hexanes and then a 25:75 mixture of ethylacetate and hexanes. Yield=0.435 g (56%). MS (APCI): 372 (M+1).

D.3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine

A 15 mL round bottom flask is charged with3-iodo-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (0.200g, 0.000539 moles), 4-(4-chloro-thiazol-2-yl)-morpholine (0.165 g,0.000808 moles), Cs₂CO₃ (0.361 g, 0.00108 moles, 2.0 equiv), Pd(dba)₂(0.0092 g, 0.0000161 moles, 0.03 equiv), PPh₃ (0.00847 gram, 0.000323moles, 0.060 equiv) and DMF (2.0 mL). Nitrogen is bubbled through thereaction mixture for 15 minutes; then, the reaction mixture is heated at130° C. overnight. The next day, the reaction mixture is partitionedbetween Et₂O and a saturated solution of NH₄Cl. The aqueous layer isextracted twice more with Et₂O. The organic extracts are combined,washed 2-3 times with H₂O, washed once with brine, and dried overNa₂SO₄. The solvents are evaporated in vacuo and the crude reactionmixture is purified via silica gel chromatography. Yield=0.1737 g (72%).¹H-NMR (CDCl₃), δ 0.87 (t, J=7 Hz, 6H), 1.14-1.37 (m, 4H), 1.74 (q, J=8Hz, 4H), 2.54 (s, 3H), 2.50 (s, 3H), 3.48 (m, 1H), 3.53 (t, J=5 Hz, 4H),3.83 (t, J=5 Hz, 4H), 6.71 (br s, 1H) ppm. LC/MS (m/z): calcd. forC₂₂H₃₀ClN₅OS (M+H)⁺: 448. found: 448.

Example 187 Preparation of1-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-piperidin-4-one

A.8-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-1,4-dioxa-8-aza-spiro[4.5]decane

100 mg of3-(2-bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.25 mmol), 182 mg of 4-piperidineethylene ketal (1.27 mmol) and 244 mgof Cs2CO3 (0.75 mmol) are put into 4.0 ml vial with 2.0 ml of THF. Thevial is capped with a Teflon® lined cap and heated at 110° C. for 3days. The reaction mixture is concentrated and applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1) to give 116 mg of the titlecompound. Yield 100%. mass spectrum (m/e): 456 (M+1). ¹H NMR (CDCl₃): δ6.69 (s, 1H), 4.05 (s, 4H), 3.70 (t, J=6.2 Hz, 4H), 3.35 (m, 1H), 2.56(s, 3H), 2.46 (s, 3H), 2.18 (s, 3H), 1.90-1.78 (m, 8H), 0.90 (t, J=7.2Hz, 6H).

B.1-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-piperidin-4-one

70 mg of8-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-1,4-dioxa-8-aza-spiro[4.5]decane(0.15 mmol) is dissolved in 10.ml of conc. HCl and stirred at roomtemperature for 2 h. The reaction mixture is neutralized with sat.NaHCO3, extracted with CH2Cl2, dried over Na2SO4 and evaporated. Thecrude product is applied onto a silica-gel chromatography column(Hexane:AcOEt=2:1) to give 33.2 mg of the title compound. Yield 52%.mass spectrum (m/e): 412 (M+1) ¹H NMR (CDCl₃): δ 6.70 (s, 1H), 3.94 (t,J=6.2 Hz, 4H), 3.35 (m, 1H), 2.67 (t, J=6.5 Hz, 4H), 2.57 (s, 3H), 2.47(s, 3H), 2.21 (s, 3H), 1.86 (m, 4H), 0.91 (t, J=7.1 Hz, 6H).

Example 188 Preparation of({5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methyl-amino)-acetaldehyde

85 mg ofN-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-N-{[1,3]dioxolan-2-ylmethyl-methylamine(0.2 mmol) is dissolved in 2 ml of conc. HCl and stirred at 50° C. for30 min. The mixture is cooled to room temperature and neutralized withsat. NaHCO3. The mixture is extracted with CH2Cl2, dried over Na2SO4 andevaporated. The crude product is applied onto a silica-gelchromatography column (CH2Cl2:MeOH=20:1) to give 73.4 mg of the titlecompound. Yield 76%. mass spectrum (m/e): 386 (M+1). 9.79 (s, 1H), 6.72(s, 1H), 4.39 (s, 2H), 3.36 (m, 1H), 3.22 (s, 3H), 2.57 (s, 3H), 2.47(s, 3H), 2.20 (s, 3H), 1.85 (m, 4H), 0.90 (t, J=7.3 Hz, 6H).

Example 189 Preparation of4-{3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-heptan-4-ol

A.3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A solution of 2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 2.17 mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole (0.72 g,2.61 mmol), Cs₂CO₃ (1.49 g, 4.57 mmol) and DMF (6 mL) is de-gassed for15 minutes with N₂. Pd(OAc)₂ (0.024 g, 0.11 mmol) and PPh₃ (0.057 g,0.22 mmol) are added and the solution is heated at 135° C. for 4 hours.The solution is diluted with CH₂Cl₂ (50 mL), washed with sat. NH₄Cl(2×50 mL), water (50 mL), filtered and concentrated. The residue ispurified by ISCO flash chromatography (30%-100% EtOAc gradient) furnishthe title compound (0.29 g, 0.84 mmol, 39%). ¹H NMR (CDCl₃) δ 2.49 (s,3H), 2.50 (s, 3H), 4.10 (s, 3H), 6.92 (d, J=9.2 Hz, 1H), 7.44 (s, 1H),7.74 (d, J=7.5 Hz, 1H), 7.85 (s, 1H). LC/MS (m/z): calcd. forC₁₅H₁₃ClN₆S (M+H)⁺: 345.1. found: 345.2.

B.1-{3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-butan-1-one

A solution of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.58 mmol), N-methoxy-N-methyl-butylamide (Wolberg, M. et. al.Chem. Europ. J. 2001, 7, 4562) (0.084 g, 0.64 mmol) in THF (3 mL) iscooled to a −78° C., and a 2.0 M solution of LDA in heptane/THF/ethylbenzene (0.58 mL, 1.16 mmol) is added. The solution is warmed to ambienttemperature, diluted with dichloromethane (20 mL), and washed with asat. NH₄Cl solution (15 mL). The organic layer is dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO flashchromatography (20%-100% EtOAc gradient) to furnish the title compound(0.11 g, 0.27 mmol, 46%). ¹H-NMR (CDCl₃), δ 1.04 (t, J=7.0 Hz, 3H),1.76-1.86 (m, 2H), 2.56 (s, 3H), 2.59 (s, 3H), 3.51 (t, J=7.1 Hz, 2H),4.15 (s, 3H), 7.36 (s, 1H), 7.49 (s, 1H), 7.90 (s, 1H) ppm. LC/MS (m/z):calcd. for C₁₉H₁₉ClN₆OS (M+H)⁺: 415.1. found: 415.3.

C.4-{3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-heptan-4-ol

A solution of1-{3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazin-8-yl}-butan-1-one(0.15 g, 0.36 mmol) and THF (5 mL) is cooled to 0° C., and a 2.0 Mpropyl magnesium bromide solution in diethylether (0.22 mL, 0.43 mmol)is added. The reaction is warmed to ambient temperature, diluted withethyl acetate (30 mL), and washed with a sat. NH₄Cl solution (30 mL).The organic layer is dried over MgSO₄, filtered, and concentrated. Theresidue is purified by ISCO flash chromatography (20%-40% EtOAcgradient) to furnish the title compound (0.016 g, 0.017 mmol, 47%).¹H-NMR (CDCl₃), δ 0.90 (t, J=7.4 Hz, 6H), 1.12-1.29 (m, 2H), 1.37-1.54(m, 2H), 1.86-2.04 (m, 4H), 2.50 (s, 3H), 2.54 (s, 3H), 4.15 (s, 3H),6.11 (bs, 1H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s, 1H) ppm. LC/MS(m/z): calcd. for C₂₂H₂₇ClN₆OS (M+H)⁺: 459.2. found: 459.3.

Example 190, 191, and 192 Preparation of7-bromo-3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine;3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine;and3-(4-bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A.8-(1-ethyl-propyl)-2,6-dimethyl-3-thiazol-5-yl-imidazo[1,2-b]pyridazine

2.41 g (7 mmol) of8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine, 3.00 gof thiazole (35.2 mmol), 378 mg of triphenylphosphine (1.44 mmol) and4.71 g of Cs2CO3 (14.5 mmol) are combined with 25 ml of DMF and N2 gasis bubbled in for 30 min. 330 mg of Pd2 dba3 (0.36 mmol) is added andthe tube is sealed. The reaction tube is heated at 130° C. overnight. Tothe reaction mixture is added water and CH2Cl2, and the CH2Cl2 layer isseparated, washed with sat. NaCl and dried over Na2SO4. The solvents areremoved in vacuo and crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1) to give 1.48 g of the titlecompound. Yield 70%. mass spectrum (m/e): 301 (M+1); ¹H-NMR (CDCl3):8.93 (s, 1H), 8.52 (s, 1H), 6.78 (s, 1H), 3.35 (m, 1H), 2.76 (s, 3H),2.66 (s, 3H), 1.86 (m, 4H), 0.89 (t, 6H, J=7.5 Hz).

B.7-bromo-3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine;3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine;and3-(4-bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

1.05 g (3.5 mmol) of8-(1-Ethyl-propyl)-2,6-dimethyl-3-thiazol-5-yl-imidazo[1,2-b]pyridazineand 1.56 g of NBS (8.75 mmol) are dissolved in 50 ml of CH₂Cl₂ andstirred at room temperature for 3 days. The reaction mixture is dilutedwith CH₂Cl₂ and washed with sat. Na₂S₂O₃ and sat. NaCl. The separatedorganic layer is dried over Na₂SO₄ and evaporated. The reaction mixtureis applied onto a silica-gel chromatography column(Hexane:AcOEt=20:1→8:1) to give three products:

149 mg of7-bromo-3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(9%);

936 mg of3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(58%); and

77 mg of3-(4-bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(6%).

7-Bromo-3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazinemass spectrum (m/e): 538 (M+1); ¹H-NMR (CDCl3): 3.45 (m, 1H), 2.71 (s,3H), 2.52 (s, 3H), 2.38 (m, 2H), 2.02 (m, 2H), 0.88 (t, 6H, J=7.5 Hz);

3-(2,4-Dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazinemass spectrum (m/e): 459 (M+1); ¹H-NMR (CDCl₃): 6.79 (s, 1H), 5.33 (m,1H), 2.57 (s, 3H), 2.55 (s, 3H), 1.87 (m, 4H), 0.90 (t, 6H, J=7.5 Hz);and

3-(4-Bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazinemass spectrum (m/e): 380 (M+1); ¹H-NMR (CDCl₃): 9.01 (s, 1H), 6.77 (s,1H), 3.35 (m, 1H), 2.55 (s, 3H), 2.54 (s, 3H), 1.87 (m, 4H), 0.91 (t,6H, J=7.5 Hz).

Example 193 Preparation of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

100 mg (0.22 mmol) of3-(2,4-Dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.22 mmol), 96 mg of morpholine (1.1 mmol) and 215 mg of Cs2CO3 (0.66mmol) are put in a 4 ml vial with dry THF, and the vial is capped with aTeflon cap. The vial is heated at 120° C. for overnight. The reactionmixture is applied onto a silica-gel chromatography column(Hexane:AcOEt:2 M NH3 in MeOH=9:3:1) to give 72.7 mg of the titlecompound. Yield 71%. mass spectrum (m/e): 465 (M+1); ¹H-NMR (CDCl3):6.73 (s, 1H), 3.87 (t, 4H, J=5.1 Hz), 3.58 (t, 4H, J=5.1 Hz), 3.35 (m,1H), 2.57 (s, 3H), 2.53 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.5 Hz).

The following compounds are prepared essentially as described in Example193. Examples 194-197 use3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.22 mmol) and the named amine. Example 198. uses7-bromo-3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineand the named amine:

MS (found) Ex Name Amine ¹H NMR (CDCl₃): δ (M + 1) 194N-{4-Bromo-5-[8-(1- Methyl- 6.75 (s, 1H), 5.85 (s, NH), 409ethyl-propyl)-2,6- amine 3.37 (m, 1H), 3.07 (d, J = 5.3 Hz,dimethyl-imidazo[1,2- 3H), 2.59 (s, 3H), b]pyridazin-3-yl]-thiazol- 2.55(s, 3H), 1.86 (m, 4H), 0.90 (t, 2-yl}-methyl-amine J = 7.2 Hz, 6H). 195N-{4-Bromo-5-[8-(1- Dimethyl- 6.72 (s, 1H), 3.36 (m, 1H), 423ethyl-propyl)-2,6- amine 3.19 (s, 6H), 2.57 (s, 3H),dimethyl-imidazo[1,2- 2.52 (s, 3H), 1.85 (m, 4H),b]pyridazin-3-yl]-thiazol- 0.90 (t, 6H, J = 7.3 Hz) 2-yl}-dimethylamine196 N-{4-Bromo-5-[8-(1- N-2- 6.71 (s, 1H), 3.76 (m, 2H), 467ethyl-propyl)-2,6- methoxy- 3.71 (m, 2H), 3.42 (s, 3H),dimethyl-imidazo[1,2- ethyl- 3.35 (s, 1H), 3.21 (s, 3H),b]pyridazin-3-yl]-thiazol- methyl- 2.57 (s, 3H), 2.53 (s, 3H),2-yl}-N-(2-methoxy- amine 1.85 (m, 4H), 0.90 (t, J = 7.3 Hz,ethyl)-methylamine 6H). 197 N-{4-Bromo-5-[8-(1- N-methyl-i- 6.72 (s,1H), 4.43 (m, 1H), 451 ethyl-propyl)-2,6- propyl- 3.36 (m, 1H), 3.0 (s,3H), dimethyl-imidazo[1,2- amine 2.57 (s, 3H), 2.54 (s, 3H),b]pyridazin-3-yl]-thiazol- 1.86 (m, 4H), 1.31 (s, 3H),2-yl}-N-methyl-i-propyl- 1.29 (s, 3H), 0.90 (t, J = 7.4 Hz, amine 6H).198 N-{5-[7-bromo-8-(1- Morpholine 3.87 (t, J = 4.5 Hz, 4H), 544ethyl-propyl)-2,6- 3.58 (t, J = 7.8 Hz, 4H), 3.43 (m,dimethyl-imidazo[1,2- 1H), 2.71 (s, 3H), 2.50 (s, b]pyridazin-3-yl]-4-3H), 2.38 (m, 2H), 2.01 (m, bromo-thiazol-2-yl}- 2H), 0.88 (t, J = 7.5Hz, 6H). morpholine

Example 199 and 200 Preparation ofN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholineandN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine

Method A

40 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineand 25 mg of CuCl (0.25 mmol) are put in a 4 ml vial with 2 ml of dryDMF and capped with a Teflon cap. The vial is heated at 120° C.overnight. The reaction mixture is filtered, washed with CH2Cl2 and thefiltrate is concentrated. The crude product mixture is applied onto asilica-gel chromatography column (Hexane:AcOEt=2:1 and Hexane:AcOEt=8:1)to give two products:

4.2 mg ofN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine(12%), and

7.2 mg ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine(22%).

N-{4-Chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholinemass spectrum (m/e): 420 (M+1); ¹H-NMR (CDCl3): 6.73 (s, 1H), 3.88 (t,4H, J=5.0 Hz), 3.57 (t, 4H, J=5.0 Hz), 3.35 (m, 1H), 2.57 (s, 3H), 2.52(s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.5 Hz.

N-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholinemass spectrum (m/e): 386 (M+1); ¹H-NMR (CDCl3): 7.75 (s, 1H), 6.70 (s,1H), 3.91 (t, 4H, J=5.0 Hz), 3.61 (t, 4H, J=5.0 Hz), 3.34 (m, 1H), 2.67(s, 3H), 2.61 (s, 3H), 1.85 (m, 4H), 0.88 (t, 6H, J=7.5 Hz).

Method BN-{4-Chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine.

A 20 L reactor flask under nitrogen is charged with 2900 ml of dry anddegassed DMF then with8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (287 g,0.836 mol), 2-morpholino-4-chlorothiazole (205.4 g, 1.01 mol, 1.2equv.), Pd(OAc)₂ (3.74 g, 7.91 mmol, 0.01 equiv.), triphenylphosphine(8.77 g, 33.1 mmol, 0.04 equiv.), Copper iodide (8 g, 41.59 mmol, 0.05equiv.) and cesium carbonate (544.9 g, 1.65 mol). The reaction mixtureis heated at 120° C. After 16 h at 120° C., 1.87 g of Pd(OAc)₂ and 4.38g of triphenylphosphine more is added. After 1 h, the mixture is cooled,quenched with NH₄Cl solution (4300 mL) and extracted with MTBE (2900mL), the aqueous phase is extracted twice more with 2000 ml of MTBE. Theorganic phases are washed with sat NaCl aq (2000 mL), then treated withcharcoal 72 g in flask bottle and filtered on Celite®. The filtrate isconcentrated under vacuum to afford 373.8 g (79.3%) of the titlecompound which is 81.4%-area HPLC analysis the rest being solvent andwith no detectable Example 200 by-product.

The following title compounds are prepared essentially as described inExamples 199 and 200 Method A:

Starting MS (found) Example # Name material ¹H NMR (CDCl₃): δ (M + 1)201 N-{4-Chloro-5-[8- N-{4-Bromo-5-[8- 6.72 (s, 1H), 3.36 (m, 378(1-ethyl-propyl)- (1-ethyl-propyl)-2,6- 1H), 3.19 (s, 6H), 2,6-dimethyl-dimethyl- 2.57 (s, 3H), 2.51 (s, 3H), imidazo[1,2- imidazo[1,2- 1.84 (m,4H), 0.90 (t, J = 7.5 Hz, b]pyridazin-3-yl]- b]pyridazin-3-yl]- 6H).thiazol-2-yl}- thiazol-2-yl}- dimethylamine dimethylamine 202N-{5-[8-(1-Ethyl- N-{4-Bromo-5-[8- 7.74 (s, 1H), 6.67 (s, 344propyl)-2,6- (1-ethyl-propyl)-2,6- 1H), 3.35 (m, 1H), dimethyl-dimethyl- 2.23 (s, 6H), 2.67 (s, imidazo[1,2- imidazo[1,2- 3H), 2.61 (s,3H), b]pyridazin-3-yl]- b]pyridazin-3-yl]- 1.84 (m, 4H), 0.90 (t, J =7.3 Hz, thiazol-2-yl}- thiazol-2-yl}- 6H). dimethyl-amine dimethylamine203 N-{4-Chloro-5-[8- N-{4-Bromo-5-[8- 6.71 (s, 1H), 3.76 (t, J = 5.3Hz, 423 (1-ethyl-propyl)- (1-ethyl-propyl)-2,6- 2H), 3.71 (t,2,6-dimethyl- dimethyl- J = 5.1 Hz, 2H), imidazo[1,2- imidazo[1,2- 3.42(s, 3H), 3.36 (m, 1H), b]pyridazin-3-yl]- b]pyridazin-3-yl]- 3.20 (s,3H), 2.58 (s, thiazol-2-yl}-N-(2- thiazol-2-yl}-N-(2- 3H), 2.52 (s, 3H),methoxy-ethyl)- methoxy-ethyl)- 1.85 (m, 4H), 0.90 (t, J = 7.1 Hz,methylamine methylamine 6H). 204 N-{5-[8-(1-Ethyl- N-{4-Bromo-5-[8- 7.72(s, 1H), 6.68 (s, 388 propyl)-2,6- (1-ethyl-propyl)-2,6- 1H), 3.80 (t, J= 5.7 Hz, dimethyl- dimethyl- 2H), 3.72 (t, J = 5.7 Hz, imidazo[1,2-imidazo[1,2- 2H), 3.42 (s, b]pyridazin-3-yl]- b]pyridazin-3-yl]- 3H),3.35 (m, 1H), thiazol-2-yl}-N-(2- thiazol-2-yl}-N-(2- 3.26 (s, 3H), 2.67(s, methoxy-ethyl)- methoxy-ethyl)- 3H), 2.61 (s, 3H), methylaminemethylamine 1.84 (m, 4H), 0.88 (t, J = 7.7 Hz, 6H). 205N-{4-Chloro-5-[8- N-{4-Bromo-5-[8- 6.71 (s, 1H), 4.48 (m, J = 7.4, 407(1-ethyl-propyl)- (1-ethyl-propyl)-2,6- 13.2 Hz, 1H), 2,6-dimethyl-dimethyl 3.34 (m, J = 7.6, 14.4 Hz, imidazo[1,2- imidazo[1,2- 1H), 3.04(s, 3H), b]pyridazin-3-yl]- b]pyridazin-3-yl]- 2.76 (s, 3H), 2.61 (s,thiazol-2-yl}-N- thiazol-2-yl}-N- 3H), 1.85 (m, 4H), methyl-i-propyl-methyl-i-propyl- 1.31 (d, J = 7.1 Hz, amine amine 6H), 0.88 (t, J = 7.3Hz, 6H). 206 N-{5-[8-(1-Ethyl- N-{4-Bromo-5-[8- 7.72 (s, 1H), 6.67 (s,371 propyl)-2,6- (1-ethyl-propyl)-2,6- 1H), 4.48 (m, 1H), dimethyl-dimethyl- 3.33 (m, 1H), 3.03 (s, imidazo[1,2- imidazo[1,2- 3H), 2.66 (s,3H), b]pyridazin-3-yl]- b]pyridazin-3-yl]- 2.60 (s, 3H), 1.84 (m, 4H),thiazol-2-yl}-N- thiazol-2-yl}-N- 1.31 (d, J = 6.8, 6H),methyl-isopropyl- methyl-i-propyl- 0.88 (t, J = 7.2 Hz, amine amine 6H).

Example 207 Preparation ofN-{5-[7-chloro-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine

50 mg ofN-{5-[7-Bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine(0.1 mmol) is dissolved in 2.0 ml of dry DMF and 31 mg of CuCl (0.3mmol) is added. The vial is capped with a Teflon® lined cap and heatedat 120° C. for overnight. The reaction mixture is applied onto asilica-gel chromatography column (Hexane:AcOEt=3:1) to give 39.2 mg ofthe title compound. Yield 87%. mass spectrum (m/e): 435 (M+1). 3.88 (t,J=4.8 Hz, 4H), 3.57 (t, J=5.1 Hz, 4H), 2.64 (s, 3H), 2.44 (s, 3H), 2.18(s, 3H), 2.00 (m, 4H), 0.88 (t, J=7.4 Hz, 6H).

Example 208 Preparation ofN-{5-[7-bromo-8-(1-ethyl-propyl)-2,6,7-trimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine

50 mg ofN-{5-[7-Bromo-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-morpholine(0.1 mmol) is dissolved in 4 ml of Et2O and cooled to −78° C. 0.09 ml ofn-BuLi 1.6M in hexane (0.15 mmol) is added at −78° C. and stirred at−78° C. for 20 min. 43 mg of iodomethane (0.3 mmol) is added to themixture and stirred at −78° C. and allowed to come to room temperatureovernight. The reaction is quenched with sat. NH4Cl and extracted withEt2O. The separated organic layer is dried over Na2SO4 and evaporated.The crude product is applied onto a silica-gel chromatography column(Hexane:AcOEt=3:1) to give 29.6 mg of the title compound. Yield 69%.mass spectrum (m/e): 414 (M+1). ¹H NMR (CDCl₃): δ 3.87 (t, J=4.6 Hz,4H), 3.56 (t, J=4.6 Hz, 4H), 3.35 (m, 1H), 2.54 (s, 3H), 2.43 (s, 3H),2.35 (s, 3H), 2.20 (s, 3H), 2.01 (m, 4H), 0.88 (m, 6H).

Example 209 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-trifluoromethyl-thiazol-2-yl}-morpholine

170 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.37 mmol) and 100 mg of sodium trifluoroacetate (0.74 mmol) aredissolved in 3 ml of DMF/toluene=2/1. N2 gas is bubbled into the mixturefor 20 min and 141 mg of CuI (0.74 mmol) is added. The vial is sealedand heated in the microwave at 210° C. for 30 min. The reaction mixtureis applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1 andCH3CN:CH2Cl2:Hexane=5:45:50) to give 64.3 mg of the title compound.Yield 38%. mass spectrum (m/e): 454 (M+1). ¹H NMR (CDCl₃): δ 6.72 (s,1H), 3.88 (m, 4H), 3.60 (m, 4H), 3.32 (m, 1H), 2.54 (s, 3H), 2.47 (s,3H), 1.85 (m, 4H), 0.89 (t, J=7.0 Hz, 6H).

Example 210 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-phenyl-thiazol-2-yl}-morpholine

50 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.11 mmol), 40 mg of phenylboronic acid (0.33 mmol) and 0.27 ml of 2 MNa2CO3aq. (0.55 mmol) are put in 2.5 ml of DME/water/EtOH=7/3/1. N2 gasis bubbled in the mixture for 20 min and 20 mg of Pd(PPh3)4 (0.017 mmol)is added. The vial is sealed and heated at 160° C. for 30 min inMicrowave. The reaction mixture are added CH2Cl2 and water and theorganic layer is separated, washed with brine, dried over Na2SO4 andevaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt=10:1) to give 27 mg of the titlecompound. Yield 54% mass spectrum (m/e): 462 (M+1). δ 8.29 (m, 1H), 7.60(m, 2H), 7.44 (m, 1H), 7.22 (m, 1H), 6.70 (s, 1H), 3.90 (t, J=4.6 Hz,4H), 3.64 (t, J=5.0 Hz, 4H), 3.36 (m, 1H), 2.52 (s, 3H), 2.09 (s, 3H),1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).

Example 211 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methoxy-thiazol-2-yl}-morpholine

100 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.22 mmol), 24 mg of sodium methoxide (0.44 mmol) and 21 mg of CuI(0.11 mmol) are put into 4 ml vial with MeOH 3 ml and capped with aTeflon® lined cap. The reaction vial is heated at 130° C. overnight. Thereaction mixture is concentrated and applied onto a silica-gelchromatography column (Hexane: THF=10:1) to give 32.8 mg of the titlecompound. Yield 36%. Mass spectrum (m/e): 416 (M+1). ¹H NMR (CDCl₃): δ6.64 (s, 1H), 3.96 (s, 3H), 3.86 (t, J=4.7 Hz, 4H), 3.53 (m, 4H), 3.34(m, 1H), 2.82 (s, 3H), 2.48 (s, 3H), 1.82 (m, 4H), 0.85 (t, J=7.4 Hz,6H).

Example 212 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-fluoro-thiazol-2-yl}-morpholine

50 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.11 mmol) is dissolved in 4 ml of diethylether and cooled to −78° C.and 0.1 ml of n-BuLi 1.6M in hexane (0.16 mmol) is added at −78° C. andstirred at −78° C. for 20 min. 104 mg of N-fluorobenzene sulfonimide(0.33 mmol) in 2 ml of toluene is added at −78° C. and stirred at roomtemperature for 1 h. sat. NH4Cl is added, and the mixture is extractedwith Et2O, dried over Na2SO4 and evaporated. The crude product isapplied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) togive 4.1 mg of the title compound. Yield 10%. Mass spectrum (m/e): 404(M+1). 6.71 (s, 1H), 3.87 (t, J=4.6 Hz, 4H), 3.55 (t, J=5.0 Hz, 4H),3.34 (m, 1H), 2.58 (s, 3H), 2.54 (s, 3H), 1.84 (m, 4H), 0.88 (t, J=7.4Hz, 6H).

Example 213 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-iodo-thiazol-2-yl}-morpholine

50 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.11 mmol), 30 mg of CF₃CO₂Na (0.22 mmol) and 42 mg of CuI (0.22 mmol)are put into 4 ml vial with DMF/toluene=2:1. The vial is capped with aTeflon cap and heated at 150° C. overnight. The reaction mixture isapplied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) togive 54 mg of the title compound. 96%. Mass spectrum (m/e): 512 (M+1).¹H NMR (CDCl₃): δ 6.71 (s, 1H), 3.87 (t, J=5.4 Hz, 4H), 3.58 (t, J=5.4Hz, 4H), 3.36 (m, 1H), 2.57 (s, 3H), 2.53 (s, 3H), 1.85 (m, 4H), 0.91(t, J=5.4 Hz, 6H).

Example 214 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-morpholin-4-yl-thiazole-4-carbonitrile

50 mg of3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.11 mmol), and 30 mg of CuCN (0.33 mmol) are put into 4 ml vial with 2ml of DMF and the vial is capped with a Teflon cap. The vial is heatedat 150° C. overnight. The reaction mixture is applied onto a silica-gelchromatography column (Hexane:AcOEt=5:1) to give 12.3 mg of the titlecompound. Yield 28%. Mass spectrum (m/e): 411 (M+1). 6.77 (s, 1H), 3.89(t, J=4.8 Hz, 4H), 3.61 (t, J=5.0 Hz, 4H), 3.32 (m, 1H), 2.62 (s, 3H),2.59 (s, 3H), 1.86 (m, 4H), 0.90 (t, J=7.4 Hz, 6H).

Example 215 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-iodo-thiazol-2-yl}-N-isopropyl-methylamine

The title compound is prepared essentially as described in Example 213,employingN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-bromo-thiazol-2-yl}-N-isopropyl-methylamineto give 17.9 mg. Yield 22%: mass spectrum (m/e): 498 (M+1). ¹H NMR(CDCl₃): δ 6.71 (s, 1H), 4.41 (m, 1H), 3.35 (m, 1H), 2.97 (s, 3H), 2.57(s, 3H), 2.53 (s, 3H), 1.84 (m, 4H), 1.29 (d, J=5.8 Hz, 6H), 0.90 (t,J=7.2 Hz, 6H).

Example 216 Preparation ofN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methoxy-thiazol-2-yl}-N-isopropyl-methylamine

The title compound is prepared essentially as described in Example 211,employingN-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-bromo-thiazol-2-yl}-N-isopropyl-methylamineto give 52.7. Yield 36%: mass spectrum (m/e): 402 (M+1). ¹H NMR (CDCl₃):δ 6.63 (s, 1H), 4.44 (m, 1H), 3.96 (s, 3H), 3.35 (m, 1H), 2.97 (s, 3H),2.57 (s, 3H), 2.50 (s, 3H), 1.83 (m, 4H), 1.29 (d, J=6.7 Hz, 6H), 0.88(t, J=8 Hz, 6H).

Example 217 and 218 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid amide and5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid N-methylamide

180 mg of8-(1-Ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.46 mmol) and 124 mg of copper(I) cyanide are put into 4 ml vial with2 ml of dry DMF. The vial is closed with a Teflon can and heated at 130°C. overnight. The crude reaction mixture is applied onto a silica-gelchromatography column (Hexane:AcOEt=1:1→1:3) to give

52.1 mg of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid amide (32%) and

7.6 mg of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid methylamide.

5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid amide: mass spectrum (m/e): 358 (M+1) ¹H NMR (CDCl₃): δ 7.21 (s,NH), 6.76 (s, 1H), 5.59 (s, NH), 3.34 (m, 1H), 2.55 (s, 3H), 2.50 (s,3H), 2.42 (s, 3H), 1.87 (m, 4H), 0.91 (t, J=7.2 Hz, 6H). and

5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid methylamide: mass spectrum (m/e): 372 (M+1). ¹H NMR (CDCl₃): 8.77(s, NH), 6.75 (s, 1H), 4.06 (s, 3H), 3.35 (m, 1H), 2.55 (s, 3H), 2.49(s, 3H), 2.43 (s, 3H), 1.87 (m, 4H), 0.91 (t, J=7.6 Hz, 6H).

Example 219 Preparation of5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid dimethylamide

5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazole-2-carboxylicacid amide (46 mg, 0.13 mmol) and 28 mg of sodium tert-Butoxide (0.30mmol) are put into 4 ml of dry DMSO and stirred at room temperature for5 min. 141 mg of iodomethane (1.0 mmol) is added and stirred at roomtemperature for 1 h.

Water is added, and the mixture is extracted with CH₂Cl₂, dried overNa2SO4 and evaporated. The crude product is applied onto a silica-gelchromatography column (Hexane:AcOEt=3:1) to give 22.3 mg of the titlecompound. Yield 45%: mass spectrum (m/e): 386 (M+1). 6.75 (s, 1H), 3.70(s, 3H), 3.35 (m, 1H), 3.21 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H), 2.41(s, 3H), 1.86 (m, 4H), 0.91 (t, J=7.4 Hz, 6H).

Example 220 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-furan-2-yl)-imidazo[1,2-b]pyridazine

A THF solution (5 mL) of 3-methylfuran (Acros, 232 mg, 2.83 mmol) iscooled to −78° C. under N₂ then treated with nBuLi (1.6 M in hexane, 1.8mL, 2.9 mmol). After addition of the nBuLi, the solution is warmed to 0°C. for 15 minutes, then to room temperature for an additional 5 minutes.The reaction mixture is then cooled to −78° C. and treated with ZnCl₂(Aldrich, 0.5 M in THF, 5.8 mL, 2.9 mmol). The resulting mixture iswarmed to room temperature and treated with8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (400 mg,1.17 mmol) and PdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 95 mg, 0.12 mmol).The mixture is heated to 60° C. for 4 hours, then poured into 1 N HCl(60 mL) and extracted with ethyl acetate (2×60 mL). The combined organicextracts are washed with aq. brine, dried over Na₂SO₄, filtered, andconcentrated. The crude residue is purified by chromatography usinghexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate inhexane) to elute the title compound as an oil pyridazine (149 mg, 43%yield). ES-MS (m/z): calc'd for C₁₈H₂₃N₃O: 297.2. found 298.5 (M+H); ¹HNMR (400 mHz, CDCl₃): δ 7.59 (d, J=1.8 Hz, 1H), 6.71 (s, 1H), 6.47 (d,J=1.8 Hz, 1H), 3.36 (m, 1H), 2.55 (s, 3H), 2.50 (s, 3H), 2.10 (s, 3H),1.92-1.79 (m, 4H), 0.90 (t, J=7.5 Hz, 6H).

Example 221 Preparation of3-(5-bromo-3-methyl-furan-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A CH₂Cl₂ solution (4 mL) of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-furan-2-yl)-imidazo[1,2-b]pyridazine(32.4 mg, 0.11 mmol) is cooled to 0° C. under a CaSO₄ drying tube andtreated with NBS (20.1 mg, 0.11 mmol). After 15 minutes at 0° C., themixture is warmed to room temperature. After an additional 10 minutes,the reaction mixture is poured into H₂O (25 mL) and extracted intoCH₂Cl₂ (2×25 mL). The combined organic extracts are washed with aq.brine, dried over Na₂SO₄, filtered, and concentrated. The crude productis purified by chromatography using hexane-ethyl acetate gradient (100%hexane to 10% ethyl acetate in hexane) to elute the title compound (26.3mg, 64% yield) as a solid. ES-MS (m/z): calc'd for C₁₈H₂₂BrN₃O: 375.1.found 376.2 (M+H); ¹H NMR (400 mHz, CDCl₃): δ 6.72 (s, 1H), 6.40 (s,1H), 3.34 (m, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.07 (s, 3H), 1.93-1.77(m, 4H), 0.89 (t, J=7.5 Hz, 6H).

Example 222 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine

A. 3-Bromo-2-methyl furan

A THF solution (10 mL) of 2,3-dibromofuran (Lancaster, 5.54 gm, 24.5mmol) under N₂ is treated with PdCl₂(PPh₃)₂ (860 mg, 1.2 mmol) andstirred for 10 minutes at room temperature. The solution is then treatedwith CH₃ZnCl (Aldrich, 2.0 M in THF, 15 mL, 30 mmol). The resultingmixture is stirred at room temperature overnight then poured into 1 NHCl and extracted into diethyl ether. The organic extract is washed withsat. NaCl, dried over Na₂SO₄, and filtered. The filtrate is thendistilled and the product is collected at 120-125° C. to give the titlecompound as a colorless oil (1.71 gm, 43% yield). ¹H NMR (400 mHz,CDCl₃): δ 7.25 (d, J=1.8 Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 2.28 (s, 3H).

B.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine

A THF solution (10 mL) of 3-bromo-2-methyl furan (prepared as describedabove) (1.06 gm, 6.58 mmol) is cooled to −78° C. under N₂ then treatedwith nBuLi (1.6 M in hexane, 4.1 mL, 6.6 mmol). After 10 minutes at −78°C., the mixture is treated with ZnCl₂ (Aldrich, 0.5 M in THF, 13.2 mL,6.6 mmol). The resulting mixture is warmed to room temperature thentreated with8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.13gm, 3.29 mmol) and PdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 257 mg, 0.31mmol). The mixture is heated to 60° C. for 4 hours, then poured intosat. NH₄Cl (50 mL) and extracted with diethyl ether (2×50 mL). Thecombined organic extracts are washed with sat. NaCl, dried over Na₂SO₄,filtered, and concentrated. The crude product is purified bychromatography using hexane-ethyl acetate gradient (100% hexane to 20%ethyl acetate in hexane) to elute the title product (685 mg, 70% yield)as an oil. ES-MS (m/z): calc'd for C₁₈H₂₃N₃O: 297.2. found 298.2 (M+H);¹H NMR (400 mHz, CDCl₃): δ 7.45 (d, J=2.0 Hz, 1H), 6.63 (s, 1H), 6.60(d, J=2.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 2.30(s, 3H), 1.88-1.75 (m, 4H), 0.86 (t, J=7.5 Hz, 6H).

Example 223 Preparation of3-(5-bromo-2-methyl-furan-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A CH₂Cl₂ solution (2 mL) of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-furan-3-yl)-imidazo[1,2-b]pyridazine(42.3 mg, 0.14 mmol) under a CaSO₄ drying tube is treated withN-bromosuccinimide (27.6 mg, 0.16 mg). After 30 minutes the reactionmixture is poured into H₂O (25 mL) and extracted into CH₂Cl₂ (2×25 mL).The combined organic extracts are washed with sat. NaCl, dried overNa₂SO₄, filtered, and concentrated. The crude product is purified bychromatography using hexane-ethyl acetate gradient (100% hexane to 12%ethyl acetate in hexane) to elute the title product (36.9 mg, 70% yield)as a white solid. ES-MS (m/z): calc'd for C₁₈H₂₂BrN₃O: 375.1. found376.3 (M+H). ¹H NMR (400 mHz, CDCl₃): δ 6.67 (s, 1H), 6.50 (s, 1H), 3.33(m, 1H), 2.53 (s, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 1.90-1.73 (m, 4H),0.86 (t, J=7.3 Hz, 6H).

Example 224 Preparation of3-(2,4-dimethyl-2H-pyrazol-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

n-BuLi (1.3 ml, 2.09 mmol) is stirred in THF (4 ml), under N₂, andcooled to −72° C. 1,4-dimethyl-¹H-pyrazole (170 mg, 2.04 mmol, in THF, 1ml) is added slowly, stirred for 5 min. then allowed to warm to ambienttemp. and stirred for 45 min. The mixture is cooled to −72° C. and azinc chloride solution (4.3 ml, 2.14 mmol, 0.5 M in toluene) added,warmed to ambient temp. and treated with8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine andPdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 40 mg, 0.05 mmol). The mixture isheated to 65° C. overnight, cooled to ambient temp., added to water andextracted twice with EtOAc. The combined organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct is purified by chromatography using a hexane-ethyl acetategradient (100% hexane to 50% ethyl acetate in hexane) to elute theproduct. The title compound is obtained (0.7% yield). ES-MS (m/z):calc'd for C₁₈H₂₅N₅: 311.4. found 312.2 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃):δ 7.51 (s, 1H), 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.53 (s, 3H),2.43 (s, 3H), 2.00 (s, 3H), 1.87 (m, 4H), 0.92 (m, 6H).

Example 225 Preparation of3-(4,5-dibromo-2-methyl-2H-pyrazol-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (300 mg, 1.4mmol), 3,4,5-tribromo-1-methyl-1H-pyrazole (700 mg, 2.1 mmol) and cesiumcarbonate (900 mg, 2.8 mmol) are stirred in DMF (5 ml) and degassed bybubbling a stream of nitrogen through the mixture. PdCl₂(PPh₃)₂ (14 mg)is added and the mixture heated to 130° C. overnight. The mixture isadded to water and extracted twice with EtOAc. The combined organicextracts are washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product is purified by chromatography using ahexane-ethyl acetate gradient (100% hexane to 20% ethyl acetate inhexane) to elute the title product (204 mg, 32% yield). ES-MS (m/z):calc'd for C₁₇H₂₁Br₂N₅: 455.2. found 455.9 (M+H)⁺. ¹H NMR (400 mHz,CDCl₃): δ 6.75 (s, 1H), 3.72 (s, 3H), 3.33 (m, 1H), 2.51 (s, 3H), 2.45(s, 3H), 1.84 (m, 4H), 0.88 (t, 6H).

Example 226 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazinebenzenesulfonic acid

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine(0.23 g, 0.57 mmol) and MeOH (1 mL) is added a solution ofbenzenesulfonic acid (0.096 g, 0.57 mmol) and MeOH (1 mL). The solutionis concentrated to furnish the title compound (0.32 g, 0.57 mmol, >99%).¹H NMR (CDCl₃) δ 0.79 (t, J=7.0 Hz, 6H), 1.59-1.82 (m, 4H), 2.06 (s,3H), 2.61 (s, 6H), 2.88 (s, 3H), 3.22-3.32 (m, 1H), 6.79 (bs, 2H), 7.25(s, 1H), 7.33-7.42 (m, 3H), 7.49 (d, J=7.9 Hz, 1H), 7.80 (d, J=7.4 Hz,2H), 7.92 (dd, J=7.4, 1.6 Hz, 1H) 8.23 (s, 1H). LC/MS (m/z): calcd. forC₂₄H₂₈N₄S (M+H)⁺: 405.2. found: 405.4.

Example 227 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-4-morpholin-4-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine

To a flask containing3-(4-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.76 mmol), morpholine (0.10 mL, 1.15 mmol), Pd₂(dba)₃ (0.035g, 0.038 mmol), and2-dicyclohexylphosphino-biphenyl-2′-(N,N-dimethyl-amino)biphenyl (0.018g, 0.046 mmol) is added 1 M LiHMDS (1.9 mL, 1.91 mmol). The solution isheated at 65° C. overnight, diluted with EtOAc (30 mL), washed withwater (20 mL), brine (20 mL), dried over MgSO₄, filtered andconcentrated. The residue is purified by ISCO (15%-30% EtOAc gradient),dissolved in Et₂O (20 mL) and extracted with 1 M HCl (2×30 mL). Theaqueous layer is washed with Et₂O (20 mL), made basic with 5 M NaOH (15mL), extracted with EtOAc (2×20 mL), the combined organic layers washedwith brine (40 mL), dried over MgSO₄, filtered and concentrated tofurnish the title compound (0.047 g, 0.12 mmol, 16%). ¹H NMR (CDCl₃) δ0.87 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.01 (s, 3H), 2.45 (s, 3H),2.49 (s, 3H), 2.99-3.05 (m, 4H), 3.28-3.37 (m, 1H), 3.84-3.88 (m, 4H),6.65 (s, 1H), 6.71 (s, 1H). LC/MS (m/z): calcd. for C₂₂H₃₀N₄OS (M+H)⁺:399.2. found: 399.2.

Example 228 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-(2-methyl-5-thiazol-2-yl-furan-3-yl)-imidazo[1,2-b]pyridazine

A THF solution (5 mL) of 2-bromothiazole (Aldrich, freshly distilled,75.0 μL, 0.84 mmol) is cooled to −78° C. under N₂ then treated withnBuLi (1.6 M in hexane, 0.52 mL, 0.83 mmol). After 15 minutes at −78°C., the mixture is treated with ZnCl₂ (Aldrich, 0.5 M in THF, 1.8 mL,0.90 mmol). The resulting mixture is warmed to room temperature thentreated with a THF slurry (1 mL) containing3-(5-bromo-2-methyl-furan-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(60.1 mg, 0.16 mmol) and PdCl₂(dppf)-CH₂Cl₂ complex (Aldrich, 22 mg,0.027 mmol). The mixture is heated overnight at 60° C., then poured intosat'd NH₄Cl and extracted with diethyl ether. The organic extract iswashed with aq. brine, dried over Na₂SO₄, filtered, and concentrated.The crude product is purified by chromatography using hexane-ethylacetate gradient (100% hexane to 20% ethyl acetate in hexane) to elutethe title compound (45.8 mg, 75% yield) as an oil. ES-MS (m/z): calc'dfor C₂₁H₂₄N₄OS: 380.17. found 381.1 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃): δ7.83 (d, J=3.5 Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 7.20 (s, 1H), 6.68 (brs, 1H), 3.35 (br s, 1H), 2.53 (s, 3H), 2.49 (s, 3H), 2.40 (s, 3H),1.90-1.76 (m, 4H), 0.88 (t, J=7.5 Hz, 6H).

Example 229 Preparation of8-(1-ethyl-propyl)-2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine;compound with methanesulfonic acid

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-(3-methyl-5-pyridin-2-yl-thiophen-2-yl)-imidazo[1,2-b]pyridazine(0.55 g, 1.36 mmol) and MeOH (6 mL) is added methane sulfonic acid(0.088 mL, 1.36 mmol). After one hour the solution is concentrated andthe solution is treated with Darco-60® for 1 hour, filtered andconcentrated to furnish the title compound (0.68 g, 1.36 mmol, >99%). ¹HNMR (CDCl₃: CD₃OD 95:5) δ 0.85 (t, J=7.4 Hz, 6H), 1.67-1.91 (m, 4H),1.96 (s, 3H), 1.97 (s, 3H), 2.20 (s, 3H), 2.61 (s, 3H), 2.90 (s, 3H),3.17-3.29 (m, 1H), 7.33 (s, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.89 (d, J=7.9Hz, 1H), 8.18 (s, 1H), 8.34 (t, J=7.9 Hz, 1H), 9.95 (bs, 1H). LC/MS(m/z): calcd. for C₂₅H₃₂N₄O₂S₂ (M+H)⁺: 405.6. found: 405.6.

Example 230 Preparation of{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophen-3-yl}-dimethyl-amine

To a −78° C. solution of dimethyl-(4-methyl-thiophen-3-yl)-amine (0.43g, 3.06 mmol) and THF (5 mL) is added 1.6 M n-BuLi (1.91 mL, 3.06 mmol).The solution is stirred for 1 hour, then 0.5 M ZnCl₂ (6.1 mL, 3.06 mmol)is added and the solution warmed to ambient temperature. After 30minutes 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.70 g, 2.04 mmol) and PdCl₂(dppf) (0.075 g, 0.10 mmol) is added andthe solution heated at 65° C. overnight. The solution is diluted withEtOAc (35 mL), washed with sat. NH₄Cl (30 mL), dried over MgSO₄,filtered and concentrated. The residue is purified by ISCO flashchromatography (15%-30% EtOAc gradient) furnish the title compound (0.13g, 0.36 mmol, 18%). ¹H NMR (CDCl₃) δ 0.86 (t, J=7.5 Hz, 6H), 1.72-1.90(m, 4H), 2.03 (s, 3H), 2.45 (s, 3H), 2.50 (s, 3H), 2.77 (s, 6H),3.28-3.37 (m, 1H), 6.63 (s, 1H), 6.65 (s, 1H). LC/MS (m/z): calcd. forC₂₀H₂₈N₄S (M+H)⁺: 357.2. found: 357.2

Example 231 Preparation of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine

A slurry of 2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine(below) (0.30 g, 1.22 mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-[1,2,4]triazole (below)(0.41 g, 1.47 mmol), KOAc (0.60 g, 6.11 mmol), TBABr (0.39 g, 1.22mmol), and NMP (3 mL) is de-gassed with N₂ for 30 minutes. Pd(OAc)₂(0.014 g, 0.061 mmol) and TDBPP (0.040 g, 0.061 mmol) are added and thesolution heated at 125° C. for 2.5 hours. The solution is diluted withEtOAc (50 mL), washed with water (3×50 mL), brine (50 mL), dried overMgSO₄, filtered and concentrated. The residue is purified by ISCO flashchromatography (20%-40% EtOAc gradient) furnish the title compound (0.30g, 0.68 mmol, 56%). ¹H NMR (CDCl₃) δ 0.89 (t, J=7.4 Hz, 6H), 1.14-1.39(m, 4H), 1.76 (q, J=16.3, 7.7 Hz, 4H), 2.51 (s, 3H), 2.52 (s, 3H),3.41-3.50 (m, 1H), 4.15 (s, 3H), 6.73 (s, 1H), 7.48 (s, 1H), 7.90 (s,1H). LC/MS (m/z): calcd. for C₂₂H₂₇ClN₆S (M+H)⁺: 443.2. found: 443.3.

Example 232 Preparation of(2-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-pyrrol-1-yl)-dimethyl-amine

Using a procedure analogous to Example 27, 1-(dimethylamino)-pyrrole(0.20 mL, 1.65 mmol), THF (4 mL), 1.6 M n-BuLi (1.10 mL, 1.73 mmol), 0.5M ZnCl₂ (3.46 mL, 1.73 mmol),3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.34 g, 0.82 mmol) and PdCl₂(dppf) (0.030 g, 0.041 mmol), furnish thetitle compound (0.17 g, 0.38 mmol, 46%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5Hz, 6H), 1.74-1.92 (m, 4H), 2.52 (s, 6H), 2.84 (s, 6H), 3.28-3.39 (m,1H), 6.21 (dd, J=4.1, 3.2 Hz, 1H), 6.38 (dd, J=4.1, 1.8 Hz, 1H), 6.68(s, 1H), 7.02 (dd, J=3.2, 1.8 Hz, 1H), 7.29 (s, 1H). LC/MS (m/z): calcd.for C₂₃H₂₈ClN₅S (M+H)⁺: 442.2. found: 442.3.

Example 233 Preparation of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 4-Chloro-thiophene-2-carbonitrile

A 22-L reaction flask is equipped with a cooling bath, air stirrer, gasaddition tube, and thermometer probe. The flask is purged with nitrogen,then charged AlCl₃ (1025 g, 7.69 moles) and CHCl₃ (6.6 L, 16.5 vol.).After cooling the mixture to 0-5° C., it is charged with 2-thiophenecarbonitrile (400 g, 3.66 moles) dropwise via an addition funnel over10-15 minutes while maintaining the temperature at ≦10° C. The mixtureis charged with Cl₂ gas (300 g, 4.23 moles, 1.16 EQ) subsurface at ≦10°C. over 1.25 hours. The progress of the reaction is monitored by GC,wherein the GC sampling method is quenching an aliquot of the reactionmixture into 6N HCl, extracting with EtOAc, drying over Na₂SO₄,filtering, and injecting the filtrate.

When the reaction is deemed complete by GC analysis [the reaction wasdeemed complete when the ratio of (sm:prod:dichloro) was approximately(1:5.8:1) by area % GC.], 6N HCl (8.0 L) is added dropwise via additionfunnel over 1.5 hours, while maintaining the temperature at ≦20° C. [TheHCl addition is extremely exothermic and evolves gas]. The reaction istransferred to a separatory funnel and the layers are separated. Afterextracting the aqueous layer with CHCl₃ (4.0 L), the chloroform layersare combined and washed with de-ionized H₂O (6.0 L). The organic layeris dried over Na₂SO₄, filtered and concentrated under vacuum to give apale yellow semi solid 575 g, 109.3%). GC (60° C. to 280° C. temperaturegradient) Area-% analysis shows ˜68% product (t_(ret)=6.5 min) withmajor impurities being the unreacted starting material (t_(ret)=5.1 min)and the dichlorinated product (t_(ret)=7.4 min). GC Method: Column: DB1;T_(injecyt)=300° C.; T_(initial)=60° C., t=2.0 min; T_(final)=280° C.,rate=18° C./min.

B. 4-Chloro-2-thiophene carboxamide

A 12-L reaction flask equipped with a cooling bath, air stirrer, andthermometer probe is charged with KOH (288.6 g, 5.143 moles) andDe-ionized H₂O (6.04 L) to form a solution that exotherms to ˜31° C.After allowing the solution to cool to ˜28.0° C., the mixture is chargedwith 4-chloro-2-thiophene carbonitrile (671.3 g, 4.675 moles)¹ followedby EtOH (675 mL). A gradual exotherm occurs upon the addition of EtOHand continues over 1-1.5 hours to ˜38° C. The reaction is stirred atambient temperature overnight. ¹ A small amount of solids wereundissolved at this point.

The reaction mixture is filtered under vacuum, washed with de-ionizedH₂O and dried to give crude product. The solids are dissolved in EtOAc(10.0 L) treated with Na₂SO₄ and Darco for 1-2 hours; then, filtered andwashed with EtOAc. The filtrate is concentrated on the Büchi untilsolids began to precipitate out at 45° C. at which time the vacuum isreleased, and the temperature is increased to 60-65° C. to redissolvethe solids. With stirring at 60° C., heptane (3.5 L) is added slowly toprecipitate solids. After stirring for 15-20 minutes at 60° C., themixture is cooled to 30-40° C. and filtered. The solids are washed withheptane (2×0.75 L), and dried to give the title compound (t_(ret)=9.9min) as a white solid (235.4 g, 31.2% 96.4 area % by GC analysis). Asecond crop is obtained from the filtrate to give 67.8 g, 9.0%; 94.5%area-% by GC analysis). The Overall yield is 303.2 g, 40.1%.

C. 4-Chloro-N-dimethylaminomethylene-2-thiophene carboxamide

A 5-L reaction flask equipped with a heating mantle, air stirrer,Dean-Stark apparatus, and thermometer probe is charged with4-chloro-2-thiophene carboxamide. (300 g, 1.856 moles) anddimethylformamide dimethylacetal (872 mL) to form a slurry thatendotherms 1-2° C. from 22-20° C. The mixture is heated gradually to 96°C. while collecting the distillate (mostly MeOH). The heating mantle isremoved, and the mixture is cooled to ≦25° C. De-ionized H₂O (3.0 L) isadded via an addition funnel and the temperature is maintained at ≦35°C. The reaction mixture is extracted with EtOAc (1×3.0 L, 1×1.5 L), thencombined the organics are washed with de-ionized H₂O (1.5 L). Theorganic phase is dried over Na₂SO₄, filtered, and concentrated undervacuum to give crude product (400 g).

The crude product is dissolved in EtOAc (320 mL, 0.8 Vol) at 50-60° C.;then, heptane (1700 mL, 4.25 Vol) is added slowly while graduallyincreasing the temperature to 70° C. A seed crystal (Lot:PP6-H00086-075-1) is added to the cloudy solution to initiateprecipitation. The resulting mixture is stirred to room temperatureovernight, then filtered and washed with heptane. The solids are driedto give the title compound (t_(ret)=13.0 min) as a white solid (329.8 g,82%; 98.2% area-% by GC analysis).

D. 5-(4-Chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole

A 3-L reaction flask equipped with a cooling bath, air stirrer, andthermometer probe is charged with4-chloro-N-dimethylaminomethylene-2-thiophene carboxamide. (155 g, 0.715moles) and HOAc (1500 mL) to form a solution. Using an ice-water coolingbath to maintain the temperature at ≦30° C., methylhydrazine (33.2 g,0.721 moles) is added dropwise via an addition funnel over 15-20 minutesto form a light yellow slurry. Gradually, the reaction is heated to 90°C. and held at 90° C. for 30 minutes. After analysis of the mixture byGC, the reaction is cooled to ˜70° C.; then, concentrated to a thickoil/slurry. De-ionized H₂O (1.67 L) is slowly added to precipitatesolids; then, the mixture is cooled to <30° C., filtered and washed withde-ionized H₂O (1.67 L). The wet solids (125.8 g) are re-dissolved inwarm MTBE (1.64 L), dried over Na₂SO₄, filtered and concentrated todryness giving the title compound as a pale yellow solid (85.8 g, 60.1%91.9% area % by GC).

E. 5-(5-Bromo-4-chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole

A 3-L reaction flask equipped with a cooling bath, air stirrer, andthermometer probe is charged with5-(4-Chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole (105.3 g, 0.527moles), ACN (1053 mL) and HOAc (105 mL) to form a solution. NBS (103.2g, 0.580 moles) is added portion-wise over 30-60 minutes whilemaintaining the temperature at ≦31° C. After stirring for 1 hour², GCanalysis indicated reaction completion. The reaction mixture is pouredinto de-ionized H₂O (2.1 L, 20 vol), stirred for 30 minutes, filtered,and washed with de-ionized H₂O (2×1 L). The product is dried in a vacuumoven at 45° C. overnight to give the title compound as a pale yellowsolid (123.0 g, 83.8%; 96.6% area-% by GC). ² The reaction temperaturedecreased after 1 hour to 26.7° C.

F. 2,6-Dimethyl-imidazo[1,2-b]pyridazine

A 3 neck 1 L round bottom flask is charged with6-methyl-pyridazin-3-ylamine (20 g, 0.18 moles), ethanol 2B (200 mL),and chloroacetone (23.7 g, 20.4 mL, 0.256 moles, 1.4 equiv). Thereaction mixture is heated at 70° C. overnight. NaHCO3 (23.2 g, 0.276moles, 1.5 equiv) is added portion wise. After most of bubblingsubsides, the reaction is heated at 100° C. overnight. The solvents areremoved in vacuo and the residue is taken up in dichloromethane andfiltered through a filter paper. The solvent is again removed in vacuo.The residue is purified using silica gel chromatography with ahexanes:ethyl acetate gradient to obtain the title compound (15.5 g,57%). ¹H-NMR (DMSO-d6), δ 2.34 (s, 3H), 2.47 (s, 3H), 7.03, (d, J=10 Hz,1H), 7.85 (d, J=10 Hz, 1H), 7.91 (s, 1H) ppm. MS (APCI): 148 (M+1).

G.3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine

A solution of 2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 2.17 mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole (0.72 g,2.61 mmol), Cs₂CO₃ (1.49 g, 4.57 mmol) and DMF (6 mL) is de-gassed for15 minutes with N₂. Pd(OAc)₂ (0.024 g, 0.11 mmol) and PPh₃ (0.057 g,0.22 mmol) are added and the solution is heated at 135° C. for 4 hours.The solution is diluted with CH₂Cl₂ (50 mL), washed with sat. NH₄Cl(2×50 mL), water (50 mL), filtered and concentrated. The residue ispurified by ISCO flash chromatography (30%-100% EtOAc gradient) furnishthe title compound (0.29 g, 0.84 mmol, 39%). ¹H NMR (CDCl₃) δ 2.49 (s,3H), 2.50 (s, 3H), 4.10 (s, 3H), 6.92 (d, J=9.2 Hz, 1H), 7.44 (s, 1H),7.74 (d, J=7.5 Hz, 1H), 7.85 (s, 1H). LC/MS (m/z): calcd. forC₁₅H₁₃ClN₆S (M+H)⁺: 345.1. found: 345.2.

H.3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine(1.50 g, 4.35 mmol) and THF (50 mL) is added 12 (1.21 g, 4.78 mmol).After 10 minutes 2 M LDA (5.44 mL, 10.87 mmol) is added. The solution isstirred for 30 minutes, quenched with water, diluted with EtOAc (100mL), washed with water (100 mL), sat. Na₂S₂O₃ (100 mL), brine (100 mL),dried over MgSO₄, filtered and concentrated. The residue is purified byISCO flash chromatography (100% EtOAc) furnish the title compound (0.61g, 1.30 mmol, 30%). ¹H NMR (CDCl₃) δ 2.50 (s, 3H), 2.55 (s, 3H), 4.14(s, 3H), 7.47 (s, 1H), 7.51 (s, 1H), 7.89 (s, 1H), LC/MS (m/z): calcd.for C₁₅H₁₂ClIN₆S (M+H)⁺: 471.0. found: 471.0.

Example 234 Preparation of3-{3-chloro-5-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-thiophen-2-yl}-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A.5-(4-Chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole

To a solution of 4-chloro-N-dimethylaminomethylene-2-thiophenecarboxamide (1.00 g, 4.62 mmol) and AcOH (1. mL) is added 70% aqueous2,2,2-trifluoroethyl-hydrazine (0.79 mL, 4.85 mmol). The solution isheated at 90° C. for 45 minutes, concentrated, dissolved in Et₂O (40mL), washed with water (30 mL), sat. NaHCO₃ (30 mL), dried over MgSO₄,filtered and concentrated to furnish the title compound (1.24 g, 4.62mmol, >99%). ¹H NMR (CDCl₃) δ 4.88 (q, J=16.8, 7.8 Hz, 2H), 7.28 (d,J=0.9 Hz, 1H), 7.31-7.33 (m, 1H), 7.94 (s, 1H). LC/MS (m/z): calcd. forC₈H₅ClF₃N₃S (M+H)⁺: 268.0. found: 268.0.

B.5-(5-bromo-4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole

To a solution of5-(4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole(1.13 g, 4.22 mmol) and AcOH (10 mL) in a sealed tube, is added Br₂(0.23 mL, 4.43 mmol). The solution is heated at 120° C. for 2 hours, and140° C. for 5 hours. The solution is concentrated, diluted with Et₂O(150 mL), washed with sat NaHCO₃ (75 mL), sat. Na₂S₂O₃ (75 mL), brine(75 mL) dried over MgSO₄, filtered and concentrated. The residue ispurified by ISCO flash chromatography (5%-15% EtOAc gradient) furnishthe title compound (1.04 g, 3.00 mmol, 71%). ¹H NMR (CDCl₃) δ 4.88 (q,J=16.0, 7.9 Hz, 2H), 7.22 (s, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. forC₈H₄BrClF₃N₃S (M+H)⁺: 345.9. found: 346.0.

C.3-{3-Chloro-5-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-thiophen-2-yl}-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 231,8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.25 g, 1.14mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole(0.47 g, 1.37 mmol), KOAc (0.56 g, 5.60 mmol), TBABr (0.37 g, 1.14mmol), and NMP (3 mL), Pd(OAc)₂ (0.013 g, 0.057 mmol) and TDBPP (0.037g, 0.057 mmol) furnish the title compound (0.43 g, 0.89 mmol, 78%). ¹HNMR (CDCl₃), δ 0.88 (t, J=7.5 Hz, 6H), 1.75-1.92 (m, 4H), 2.52 (s, 3H),2.53 (s, 3H), 3.27-3.36 (m, 1H), 4.98 (q, J=15.7, 7.9 Hz, 2H), 6.74 (s,1H), 7.45 (s, 1H), 8.03 (s, 1H). LC/MS (m/z): calcd. for C₂₁H₂₂ClF₃N₆S(M+H)⁺: 483.1. found: 483.2.

Example 235 Preparation of3-[5-(2-tert-butyl-2H-[1,2,4]triazol-3-yl)-3-chloro-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 1-tert-Butyl-5-(4-chloro-thiophen-2-yl)-1H-[1,2,4]triazole

Using a procedure analogous to Example 234A,4-chloro-N-dimethylaminomethylene-2-thiophene carboxamide (5.00 g, 23.07mmol) and AcOH (50. mL), tert-butylhydrazine hydrochloride (3.16 g,25.38 mmol) furnish the title compound (0.20 g, 0.83 mmol, 3.6%). ¹H NMR(CDCl₃) δ 1.63 (s, 9H), 7.07 (d, J=1.3 Hz, 1H), 7.51 (d, J=1.3 Hz, 1H),8.08 (s, 1H).

B.5-(5-Bromo-4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole

Using a procedure analogous to Example 249B,1-tert-butyl-5-(4-chloro-thiophen-2-yl)-¹H-[1,2,4]triazole (0.20 g, 0.83mmol), AcOH (3 mL) and Br₂ (0.051 mL, 0.99 mmol) furnish the titlecompound (0.27 g, 0.83 mmol, >99%). ¹H NMR (CDCl₃) δ 1.62 (s, 9H), 7.42(s, 1H), 8.08 (s, 1H). LC/MS (m/z): calcd. for C₁₀H₁₁BrClN₃S (M+H)⁺:320.0. found: 320.0.

C.3-[5-(2-tert-Butyl-2H-[1,2,4]triazol-3-yl)-3-chloro-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure analogous to Example 231,8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 g, 0.68mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-¹H-[1,2,4]triazole(0.20 g, 0.82 mmol), KOAc (0.34 g, 3.42 mmol), TBABr (0.22 g, 0.68mmol), and NMP (3 mL), Pd(OAc)₂ (0.0077 g, 0.034 mmol) and TDBPP (0.022g, 0.034 mmol) furnish the title compound (0.039 g, 0.085 mmol, 13%). ¹HNMR (CDCl₃), δ 0.87 (t, J=7.5 Hz, 6H), 1.65 (s, 9H), 1.73-1.91 (m, 4H),2.51 (s, 6H), 3.26-3.37 (m, 1H), 6.69 (s, 1H), 7.65 (s, 1H), 8.11 (s,1H). LC/MS (m/z): calcd. for C₂₃H₂₉ClN₆S (M+H)⁺: 457.2. found: 457.3.

Example 236 Preparation of3-(3-chloro-5-[1,2,4]triazol-1-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A.3-(3-Chloro-5-iodo-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(2 g, 6 mmol) in 10 mL of anhydrous CH₃CN under nitrogen was addedportionwise NIS (1.6 g, 7.2 mmol). The reaction mixture is stirred atreflux for 14 hours. After cooling, the solvent is concentrated undervacuum, the residue is dissolved in EtOAc and washed with H₂O, 5%solution of sodium bisulfite, H₂O and brine. The organic layer is driedover magnesium sulfate, filtered and concentrated under vacuum. Thecrude residue is purified by silica gel chromatography using hex/EtOAc8:2 as eluent mixture, to obtain 2.4 g (90%) of the title compound; massspectrum 460 (M+1); 1H-NMR (CDCl₃, 300 MHz) δ 7.24 (s, 1H), 6.71 (s,1H), 3.32 (q, 1H, J=7.2 Hz), 2.52 (s, 3H), 2.49 (s, 3H), 1.84 (q, 4H,J=7.2 Hz); 0.88 (t, 6H, J=7.2 Hz) ppm.

B.3-(3-Chloro-5-[1,2,4]triazol-1-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(3-chloro-5-iodo-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.65 mmol), 1H-triazole (0.047 μg, 0.69 mmol), CuI (0.0062,0.033 mmol), Cs₂CO₃ (0.45 g, 1.37 mmol) and DMF (3 mL) is added(1S,2S)-(+)-N,N′-dimethylcyclohexane-1,2-diamine (0.014 mL, 0.098 mmol).The solution is heated at 112° C. overnight, diluted with CH₂Cl₂ (10 mL)and filtered thru Celite® and concentrated. The residue is purified byISCO flash chromatography (30%-40% EtOAc gradient furnish the titlecompound (0.028 g, 0.070 mmol, 11%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz,6H), 1.75-1.92 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.35 (m, 1H),6.72 (s, 1H), 7.22 (s, 1H), 8.10 (s, 1H), 8.50 (s, 1H). LC/MS (m/z):calcd. for C₁₉H₂₁ClN₆S (M+H)⁺: 401.1. found: 401.2.

Example 237 Preparation of3-[3-chloro-5-(2,5-dimethyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.30 g, 0.72 mmol) and THF (5 mL) is added 1.7 M tert-BuLi (0.47 mL,0.80 mmol). After 15 minutes MeI (0.052 mL, 0.83 mmol) is added and thesolution warmed to ambient temperature. The solution is diluted withEtOAc (40 mL), washed with brine (40 mL), dried over MgSO₄, filtered andconcentrated. The solution is recrystallized from acetone:hexane furnishthe title compound (0.13 g, 0.30 mmol, 42%). ¹H NMR (CDCl₃) δ0.88 (t,J=7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.36 (s, 3H), 2.51 (s, 6H), 3.27-3.39(m, 1H), 3.40 (s, 3H), 6.72 (s, 1H), 8.02 (s, 1H). LC/MS (m/z): calcd.for C₂₁H₂₅ClN₆S (M+H)⁺: 429.2. found: 429.2.

Example 238 Preparation of3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. N-(6-Methoxy-pyridazin-3-yl)-2,2-dimethyl-propionamide

3-Chloro-6-methoxy-pyridazine (10.0 g, 69.18 mmol) is mixed with2,2-dimethyl-propionamide (8.40 g, 83.01 mmol), BINAP (2.15 g, 3.46mmol), Cs₂CO₃ (33.8 g, 103.77 mmol) in 1,4-dioxane (150 mL). It isdegassed by passing N₂ through for 10 min at rt. Pd₂(dba)₃ (3.16 g, 3.46mmol) is added and the resulting mixture is refluxed overnight. Themixture is cooled to rt, diluted with EtoAc (150 mL); filtered throughsilica gel; washed with EtOAc (2×150 mL). The filtrate is washed withH2O (2×300 mL); dried with MgSO₄; filtered and concentrated.Purification of the crude material by silica gel chromatography givesthe title compound (6.59 g, 31.53 mmol, 46%). ¹H NMR (CDCl3): δ. 1.35(s, 9H), 4.08 (s, 3H), 7.01 (d, J=9.7 Hz, 1H), 8.41 (d, J=9.7 Hz, 1H),8.44 (bs, 1H). ES-MS (m/z): calcd for C₁₀H₁₅N₃O₂ (M+H)⁺: 210.3. found:210.1.

B.N-[4-(1-Ethyl-propyl)-6-methoxy-pyridazin-3-yl]-2,2-dimethyl-propionamide

Using a procedure analogous to Example 6a, fromN-(6-methoxy-pyridazin-3-yl)-2,2-dimethyl-propionamide (6.09 g, 29.14mmol) and a Grignard reagent prepared from 3-pentyl bromide (18.1 mL,160.3 mmol) and Mg (3.84 g, 160.26 mmol) gives the title compound (5.32g, 19.08 mmol, 65%). ¹H NMR (CDCl₃): δ. 0.84 (t, J=7.5 Hz, 6H), 1.36 (s,9H), 1.50-1.72 (m, 4H), 3.50-3.70 (m, 1H), 4.07 (s, 3H), 6.96 (s, 1H).ES-MS (m/z): calcd for C₁₅H₂₅N₃O₂ (M+H)⁺: 280.4. found: 280.2.

C. 4-(1-Ethyl-propyl)-2-methoxy-6-methyl-pyrrolo[1,2-b]pyridazine

A solution ofN-[4-(1-ethyl-propyl)-6-methoxy-pyridazin-3-yl]-2,2-dimethyl-propionamide(5.32 g, 19.08 mmol) in EtOH (250 mL) is treated with ZnCl₂ (26.0 g,190.8 mmol) and refluxed for 48 h. The reaction is cooled to rt andconcentrated. The residue is taken up with EtOAc (250 mL), and H₂O (100mL). It is washed with H₂O (2×100 mL); dried with Na₂SO₄; filtered andconcentrated. The residue is then dissolved in EtOAc (80 mL), reactedwith chloroacetone (1.6 mL, 20.03 mmol.) at reflux overnight. While itis hot, NaHCO₃ (8.10 g) is added and the reaction is refluxed for 1 h.It is cooled to rt and filtered through silica gel washed with EtOAc andconcentrated. Purification of the crude material by chromatography givesthe title compound (0.48 g, 2.07 mmol, 11%). ¹H NMR (CDCl₃): δ. 0.84 (t,J=7.5 Hz, 6H), 1.69-1.869 (m, 4H), 2.45 (s, 3H), 3.19-3.30 (m, 1H), 3.94(s, 3H), 6.39 (s, 1H), 7.49 (s, 1H). ES-MS (m/z): calcd for C₁₄H₂₀N₂O(M+H)⁺: 233.3. found: 234.1.

D.3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A solution of4-(1-ethyl-propyl)-2-methoxy-6-methyl-pyrrolo[1,2-b]pyridazine (74.8 mg,0.32 mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole (107.5mg, 0.38 mmol), TDBPP (10.4 mg, 0.016 mmol), tetrabutylammonium bromide(103.0 mg, 0.32 mmol), KOAc (158 mg, 1.61 mmol) in NMP (15 mL) is purgedwith N2 for 5 min. Pd(OAc)₂ (3.6 mg, 0.016 mmol) is added and theresulting mixture is stirred at 125° C. for 6 h. The reaction is cooledto rt, and diluted with EtOAc (10 mL); filtered through silica gel;washed with EtOAc (3×30 mL). The filtrate is washed with H2O (3×30 m);dried with Na2SO4, filtered and concentrated. Purification of the crudematerial by silica gel chromatography gives the title compound (0.1062g, 0.2469 mmol, 77%). 1H NMR (CDCl₃): δ. 0.89 (t, J=7.6 Hz, 6H),1.75-1.90 (m, 4H), 2.52 (s, 3H), 3.22-3.38 (m, 1H), 3.93 (s, 3H), 4.15(s, 3H), 6.52 (s, 1H), 7.48 (s, 1H), 7.91 (s, 1H). ES-MS (m/z): calcdfor C₂₀H₂₃ClN₆OS (M+H)⁺: 431.9. found: 431.3.

Example 239 Preparation of3-[3-chloro-5-(5-fluoro-2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a −78° C. solution of3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.40 g, 0.72 mmol) and THF (8 mL) is added 1.7 M tert-BuLi (0.47 mL,0.80 mmol). After 30 minutes the solution is transferred via a cannulainto a solution of N-fluorobenzenesulfonamide (0.40 g, 1.25 mmol) andTHF. After 30 minutes the solution warmed to ambient temperature. Thesolution is diluted with EtOAc (40 mL), washed with water (30 mL), brine(30 mL), dried over MgSO₄, filtered and concentrated. The solution ispurified by ISCO (20%-30% EtOAc gradient) furnish the title compound(0.068 g, 0.16 mmol, 16%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H),1.71-1.93 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.26-3.36 (m, 1H), 4.08(d J=2.7 Hz, 3H), 6.75 (s, 1H), 7.97 (s, 1H). LC/MS (m/z): calcd. forC₂₀H₂₂ClFN₆S (M+H)⁺: 433.2. found: 433.2.

Example 240 Preparation of Preparation of3-(4,5-dibromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(5.92 g, 14.34 mmol) and trifluoroacetic acid (40 mL) and 98% H₂SO₄ (10ml) is added NBS (3.83 g, 21.15 mmol). After 10 minutes the solution ispoured into ice, and made basic with 5M NaOH. The slurry is extractedwith EtOAc (3×100 mL), the combined organic layers washed with water(2×400 mL), brine (400 mL), dried over MgSO₄, filtered and concentratedto furnish the title compound (6.61 g, 13.44 mmol, 94%). ¹H NMR (CDCl₃)δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.92 (m, 4H), 2.47 (s, 3H), 2.52 (s, 3H),3.25-3.34 (m, 1H), 6.72 (s, 1H). LC/MS (m/z): calcd. for C₁₇H₁₈Br₂ClN₃S(M+H)⁺: 489.9. found: 490.0.

Example 241 Preparation of3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using a procedure similar to Example 76,3-(4,5-dibromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(1.83 g, 3.72 mmol), 1.6 M n-BuLi (2.56 mL, 4.09 mmol), and THF (30 mL)furnish the title compound (1.05 g, 2.54 mmol, 68%). ¹H NMR (CDCl₃) δ0.87 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.48 (s, 3H), 2.51 (s, 3H),3.27-3.36 (m, 1H), 6.71 (s, 1H), 7.55 (s, 1H). LC/MS (m/z): calcd. forC₁₇H₁₉BrClN₃S (M+H)⁺: 412.0. found: 412.1.

Example 242 Preparation of3-(1-methyl-3-phenyl-1H-pyrazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 1-methyl-3-phenyl-1H-pyrazole and 1-methyl-5-phenyl-¹H-pyrazole

Sodium hydride (60% dispersion in mineral oil, 0.83 g, 20.8 mmol) issuspended in THF (45 ml) and stirred under a nitrogen atmosphere.3-Phenyl pyrazole (2.5 g, 17.3 mmol dissolved in THF, 15 ml) is addedslowly, stirred for 30 minutes then iodomethane (1.3 ml, 20.8 mmol)added and stirred for 3 hrs. The reaction is added to water andextracted twice with ethyl acetate. The combined organic extracts areished with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product is purified by chromatography using a hexane-ethyl acetategradient (100% hexane to 40% ethyl acetate in hexane) to elute the titlecompound. Obtained is a mixture of 1-methyl-3-phenyl-1H-pyrazole and1-methyl-5-phenyl-¹H-pyrazole (2.6 g, 95% yield).

B. 4-Bromo-1-methyl-3-phenyl-¹H-pyrazole and4-bromo-1-methyl-5-phenyl-¹H-pyrazole

The mixture of isomers, 1-methyl-3-phenyl-1H-pyrazole and1-methyl-5-phenyl-¹H-pyrazole (1.0 g, 6.3 mmol) and NBS (1.1 g, 6.3mmol) are combined in acetonitrile (25 ml), stirred and heated to 70° C.for 1 hr. The solution is concentrated and the crude product is purifiedby chromatography using a hexane-ethyl acetate gradient (100% hexane to25% ethyl acetate in hexane) to elute4-bromo-1-methyl-3-phenyl-¹H-pyrazole (504 mg, 34% yield) and4-bromo-1-methyl-5-phenyl-1H-pyrazole (295 mg, 20% yield), respectively:

¹H NMR: (400 mHz, DMSO): δ 8.01 (s, 1H), 7.95 (d, 2H), 7.41 (t, 2H),7.38 (d, 1H), 3.85 (s, 3H).

¹H NMR: (400 mHz, DMSO): δ 7.63 (s, 1H), 7.50 (m, 5H) 3.77 (s, 3H).

C.3-(1-Methyl-3-phenyl-1H-pyrazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (160 mg, 0.73mmol), 4-bromo-1-methyl-3-phenyl-¹H-pyrazole (250 mg, 1.1 mmol) andcesium carbonate (490 mg, 1.50 mmol) are stirred in DMF (5 ml) anddegassed by bubbling a stream of nitrogen through the mixture.PdCl₂(PPh₃)₂ (15 mg) is added and the mixture is heated to 130° C.overnight. The mixture is added to water and extracted twice with ethylacetate. The combined organic extracts are dried over Na₂SO₄, filteredand concentrated. The crude product is purified by chromatography usinga hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate inhexane) to elute the title compound (17.5 mg, 4% yield). ES-MS (m/z):calc'd for C₂₃H₂₇N₅: 373.5. found 374.2 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃):δ 7.68 (s, 1H), 7.37 (m, 2H), 7.20 (m, 3H), 6.59 (s, 1H), 4.04 (s, 3H),3.36 (m, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.82 (m, 4H), 0.86 (t, 6H).

Example 243 Preparation of3-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using the procedure analogous to Example 242, from8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (160 mg, 0.73mmol), 4-bromo-1-methyl-5-phenyl-¹H-pyrazole (250 mg, 1.1 mmol), cesiumcarbonate (490 mg, 1.50 mmol) and PdCl₂(PPh₃)₂ (15 mg) in DMF (5 ml)gives the title compound (18 mg, 4% yield). ES-MS (m/z): calc'd forC₂₃H₂₇N₅: 373.5. found 374.2 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃): δ 7.85 (s,1H), 7.32 (m, 3H), 7.23 (m, 2H), 6.55 (s, 1H), 3.94 (s, 3H), 3.27 (m,1H), 2.38 (s, 3H), 2.03 (s, 3H), 1.76 (m, 4H), 0.83 (t, 6H).

Example 244 Preparation of 3-(3,5-dimethylisoxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using the procedure analogous to Example 242, from8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90mmol), 4-bromo-3,5-dimethyl isoxazole (Alfa, 320 mg, 1.8 mmol), cesiumcarbonate (880 mg, 2.70 mmol) and PdCl₂(PPh₃)₂ (25 mg) in DMF (5 ml),heated at 130 for 4 hrs, then overnight at ambient temperature gives thetitle compound (65 mg, 23% yield). ES-MS (m/z): calc'd for C₁₈H₂₄N₄O:312.4. found 313.2 (M+H)⁺. ¹H NMR (400 mHz, CDCl₃): δ 6.68 (s, 1H), 3.32(m, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 1.82(m, 4H), 0.87 (m, 6H).

Example 245 Preparation of3-(3-methyl-5-phenyl-isoxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

A. 4-Bromo-3-methyl-5-phenyl isoxazole

3-Methyl-5-phenyl isoxazole (Synthesis, 1997, 439-442) (1.0 g, 6.3 mmol)and N-bromosuccinimide (1.2 g, 6.9 mmol) are combined together in aceticacid (30 ml) and heated to reflux with stirring for 2 hrs. The solutionis added to water and extracted twice with ethyl acetate. The combinedorganic extracts are washed with sodium bicarbonate (sat'd) and sat.NaCl then dried over Na₂SO₄, filtered and concentrated. The crudeproduct is purified by chromatography using a hexane-ethyl acetategradient (100% hexane to 10% ethyl acetate in hexane) to elute the titlecompound (1.5 g, 100% yield). ¹H NMR (400 mHz, CDCl₃): δ 8.02 (m, 2H),7.49 (m, 3H), 6.34, 2.35 (s, 3H).

B.3-(3-Methyl-5-phenyl-isoxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Using the procedure analogous to Example 257,8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90mmol), 4-bromo-3-methyl-5-phenyl isoxazole (430 mg, 1.8 mmol), cesiumcarbonate (880 mg, 2.70 mmol) and PdCl₂(PPh₃)₂ (25 mg) in DMF (5 ml) arecombined and heated at 130° C. for 5 hrs to give the title compound (65mg, 23% yield). ES-MS (m/z): calc'd for C₂₃H₂₆N₄O: 374.5. found 375.1(M+H)⁺. ¹H NMR (400 mHz, CDCl₃): δ 7.50 (d, 2H), 7.31 (m, 3H), 6.69 (s,1H), 3.39 (m, 1H), 2.48 (s, 3H), 2.20 (s, 6H), 2.33 (s, 3H), 1.84 (m,4H), 0.88 (m, 6H).

Example 246{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-dipropyl-amine

35 mg of3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.09 mmol) and 45 mg of di-n-propylamine (0.44 mmol) and 57 mg ofcesium carbonate (0.18 mmol) are place into 4 ml reaction vial with 3 mlof dry THF and the vial is capped with a Teflon cap. The reaction vialis heated at 100° C. for 4 h. The reaction mixture is transferred intomicrowave reaction vessel and sealed. The reaction mixture is heated at160° C. for 30 min by microwave. The mixture is concentrated and appliedonto silica-gel chromatography column (Hexane:AcOEt=3:1) to give thetitle compound. 5.3 mg (14%); mass spectrum (m/e): 414; ¹H-NMR (CDCl₃):5.59 (s, 1H), 3.45 (m, 4H), 3.36 (m, 1H), 2.57 (s, 3H), 2.47 (s, 3H),2.17 (s, 3H), 1.80 (m, 8H), 0.99 (t, 6H, J=7.5 Hz), 0.89 (t, 6H, J=9.4Hz).

Example 247N-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-chloro-thiazol-2-yl}-dimethylamine,mesylate salt

89 mg ofN-{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-chloro-thiazol-2-yl}-dimethylamine(0.236 mmol) is dissolved in 2.0 ml of ethylacetate and 0.236 ml of 1Mmethanesulfonic acid in ethylacetate (0.236 mmol) is added. The solventsare removed under N₂ gas and precipitated crystals are collected, washedwith Et2O and dried. 92 mg (83%); mass spectrum (m/e): 378 (M+1); ¹H-NMR(CDCl₃): 7.30 (s, 1H), 3.67 (m, 1H), 3.22 (s, 6H), 2.93 (s, 3H), 2.78(s, 3H), 2.78 (s, 3H), 2.71 (s, 3H), 1.95 (m, 2H), 1.82 (m, 2H), 0.96(t, 6H, J=7.3 Hz).

Example 248 Preparation of{5-Bromo-4-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-oxazol-2-yl}-dimethyl-amine

A.8-(1-Ethyl-propyl)-2,6-dimethyl-3-oxazol-4-yl-imidazo[1,2-b]pyridazine

500 mg of8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.46mmol), 622 mg of oxazole (9.0 mmol), 79 mg of triphenylphosphine (0.3mmol) and 989 mg of cesium carbonate (3.03 mmol) are placed intoreaction vial with 7 ml of dry DMF. N₂ gas is bubbled into the mixturefor 30 min and 67 mg of Pd₂ dba₃ (0.07 mmol) is added. The reaction vialis capped with a Teflon cap and stirred at 130° C. for 3 days. Thereaction mixture is diluted with dichloromethane, washed with sat NaCl,dried over Na₂SO₄ and evaporated. The crude product is applied onto asilica-gel chromatography column (Hexane:EtOAc=3:1) to give the titlecompound 172 mg (42%); mass spectrum (m/e): 285; ¹H-NMR (CDCl₃): 8.04(s, 1H), 7.97 (s, 1H), 6.78 (s, 1H), 3.35 (m, 1H), 2.80 (s, 3H), 2.65(s, 3H), 1.86 (m, 4H), 0.88 (t, 6H).

B.3-(2,5-Dibromo-oxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

172 mg of8-(1-ethyl-propyl)-2,6-dimethyl-3-oxazol-4-yl-imidazo[1,2-b]pyridazine(0.60 mmol) and 270 mg of NBS (1.51 mmol) are dissolved in 8.0 ml ofdichloromethane and stirred at room temperature overnight. The reactionmixture is concentrated and applied onto a silica-gel chromatographycolumn (Hexane:EtOAc=3:1) to give 70 mg of the title compound (26%);mass spectrum (m/e): 442; ¹H-NMR (CDCl₃): 6.82 (s, 1H), 3.32 (m, 1H),2.59 (s, 3H), 2.54 (s, 3H), 1.86 (m, 4H), 0.89 (t, 6H, J=7.4 Hz).

C.{5-Bromo-4-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-oxazol-2-yl}-dimethyl-amine

67 mg of3-(2,5-Dibromo-oxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.15 mmol), 146 mg of cesium carbonate (0.45 mmol) and 3.0 ml ofdimethylamine 2.0M in THF (6 mmol) are placed into a 4 ml of reactionvial and the vial is capped with a Teflon cap. The reaction vial isheated at 130° C. overnight. The reaction mixture is concentrated andapplied onto a silica-gel chromatography column (Hexane:AcOE t=3:1) togive 53 mg of the title compound (87%); mass spectrum (m/e): 406; ¹H-NMR(CDCl₃): 6.72 (s, 1H), 3.37 (m, 1H), 3.15 (s, 6H), 2.58 (s, 3H), 2.53(s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.2 Hz).

Example 249 Preparation of3-[3-chloro-4-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a flask of3-(4-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.20 g, 0.49 mmol) is added 0.5 g/mL Reike® Zn (1.3 mL, 0.97 mmol). Theslurry is heated at 65° C. for 1 hour, placed in a centrifuge for 5minutes, and the solution transferred to a flask containing5-bromo-1-methyl-¹H-[1,2,4]triazole (0.12 g, 0.73 mmol) and PdCl2(dppf)(0.018 g, 0.024 mmol). The solution is heated at 65° C. overnight,diluted with EtOAc (20 mL), washed with sat. NH₄Cl (15 mL), dried overMgSO₄, filtered and concentrated. The residue is purified by ISCO flashchromatography (20%-50% EtOAc gradient) furnish the title compound(0.018 g, 0.043 mmol, 9%). ¹H NMR (CDCl₃) δ 0.87 (t, J=7.5 Hz, 6H),1.74-1.92 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.95(s, 3H), 6.72 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H). LC/MS (m/z): calcd.for C₂₀H₂₃ClN₆S (M+H)⁺: 415.2. found: 415.3.

Example 250 Preparation of{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-trifluoromethyl-thiazol-2-yl}-dimethyl-amine

A.8-(1-Ethyl-propyl)-2,6-dimethyl-3-thiazol-5-yl-imidazo[1,2-b]pyridazine

Iodoimidazopiridazine (6.75 g, 19.7 mmol), triphenylphosphine (1.03 g,3.94 mmol), Cs₂CO₃ (12.84 g, 39.4 mmol) and Pd₂(dba)₃ (900 mg, 0.98mmol) are put into a sealed tube with 65 mL of dry DMF and N₂ gas isbubbled into the mixture for 5 minutes. Thiazole (8.36 g, 6.7 mL, 98.4mmol) is added, and the mixture is heated at 130° C. overnight. Themixture is cooled to r.t. and quenched by addition of NH₄Cl saturatedsolution (200 mL). The mixture is extracted with Et₂O (3×100 mL) and theorganic layers washed with water (2×100 mL) and sat. NaCl (100 mL),dried over MgSO₄ and concentrated. The crude product is purified byflash chromatography on silica gel (eluent; hexane:EtOAc=4:1) to give3.80 g of the title compound (Yield: 64%). ESIMS: m/z 301 [M+H]⁺.

B.3-(2,4-Dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-thiazol-5-yl-imidazo[1,2-b]pyridazine.(3.80 g, 12.6 mmol) in CH₃CN (55 mL) at room temperature is added NBS(5.18 g, 29.1 mmol), and the mixture is stirred at room temperature for3 hours. A white precipitate is formed that is filtered in vacuo, togive 4.86 g of the title compound (Yield: 84%). ESIMS: m/z 459, 461[M+H]⁺.

C.3-(4-Bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of3-(2,4-dibromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(4.86 g, 10.6 mmol) in THF (150 mL) under N₂ atmosphere at −78° C., BuLi(6.63 mL 1.6 M in hexane, 10.6 mmol) is added dropwise for a period of10 minutes. The mixture is stirred at −78° C. for 30 minutes. Water isadded, and the mixture is extracted with Et₂O (3×100 mL), dried overMgSO₄ and concentrated in vacuo. Crude product is purified by flashchromatography on silica gel (eluent hexane:EtOAc 5:1) to give 3.28 g ofthe title compound (Yield: 82%). ESIMS: m/z 379, 381 [M+H]⁺.

D.8-(1-Ethyl-propyl)-2,6-dimethyl-3-(4-trifluoromethyl-thiazol-5-yl)-imidazo[1,2-b]pyridazine

To a solution of3-(4-bromo-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(2.45 g, 6.5 mmol) in NMP (35 mL) in a sealed tube is added FSO₂CF₂CO₂Me(2.5 g, 1.65 mL, 13 mmol) and CuI (2.48 g, 13 mmol). N₂ gas is bubbledinto the mixture for 5 minutes, and the mixture is heated at 120° C. for9 hours. After cooling to room temperature, water (100 mL) and NaClsaturated solution (100 mL) are added to the mixture. The mixture isextracted with Et₂O (5×80 mL); washed with water (2×100 mL), and driedover MgSO₄ and concentrated. The crude product is purified by flashchromatography on silica gel (eluent hexane:EtOAc 5:1) to obtain 960 mgof the title compound (Yield: 40%). ESIMS: m/z 369 [M+H]⁺.

E.3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

To a solution of8-(1-ethyl-propyl)-2,6-dimethyl-3-(4-trifluoromethyl-thiazol-5-yl)-imidazo[1,2-b]pyridazine(915 mg, 2.48 mmol) in 40 mL of THF under N₂ atmosphere al −78° C., BuLi(1.86 mL 1.6 M in hexane, 2.98 mmol) is slowly added. The mixture isstirred at −78° C. for 30 minutes. Then, a solution of CBr₄ (989 mg,2.98 mmol) in 3 mL of THF is added, and the mixture is stirred at −78°C. for 45 minutes. The reaction is quenched by addition of NH₄Clsaturated solution (50 mL), extracted with Et₂O (2×50 mL), dried overMgSO₄, and concentrated in vacuo. Crude product is purified by flashchromatography on silica gel (eluent CH₂Cl₂) to obtain 685 mg of thetitle compound (Yield: 62%). ¹H NMR (CDCl₃): δ0.86 (t, J=7.5 Hz, 6H),1.82 (m, 4H), 2.45 (s, 3H), 2.51 (s, 3H), 3.27 (m, 1H), 6.74 (s, 1H).ESIMS: m/z 447, 449 [M+H]⁺.

F.{5-[8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-trifluoromethyl-thiazol-2-yl}-dimethyl-amine

100 mg of3-(2-Bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine(0.22 mmol) and 218 mg of cesium carbonate (0.66 mmol) are placed in 4ml reaction vial and 3 ml of dimethylamine 2 M in THF is added. Thereaction vial is capped with a Teflon cap and heated at 120° C.overnight. The reaction mixture is filtered and concentrated and appliedonto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 85 mgof the title compound. Yield 94%. mass spectrum (m/e): 412 (M+1).

Example 251 Preparation of8-(1-Ethyl-propyl)-2,6-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-4-trifluoromethyl-thiazol-5-yl]-imidazo[1,2-b]pyridazine

164 mg of 1-Methyl-1,2,4-triazole (1.96 mmol) is dissolved in 2 ml ofTHF and cooled to −78° C. 0.8 ml of 2.5M n-butyllithium in hexane (1.96mmol) is added slowly and stirred at −78° C., warmed up to roomtemperature and stirred at r.t. for 15 min and cooled to −78° C. 3.96 mlof 0.5 M ZnCl₂ in THF (1.98 mmol) is added and stirred at roomtemperature for 15 min. 180 mg of3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineand 54 mg of PdCl2(pddf) (0.06 mmol) are added. The vial is capped witha Teflon cap and heated at 80° C. overnight. NH₄Cl aq. is added toquench the reaction and the mixture is extracted by CH₂Cl₂, dried overNa2SO4 and evaporated. The crude product is applied onto silica-gelchromatography column (Hexane:AcOEt=3:1) to give 119 mg of the titlecompound. Yield 58%. mass spectrum (m/e): 449 (M+1).

Example 252 Preparation of8-(1-Ethyl-propyl)-6-methyl-3-(3-methyl-thiophen-2-yl)-2-trifluoromethyl-imidazo[1,2-b]pyridazine

A.8-(1-Ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

α-Bromotrifluoroacetone (402 mg, 2.93 mmol) is added to a dry 10 mLmicrowave reaction tube containing4-(1-ethyl-propyl)-6-methyl-pyridazin-3-ylamine (500 mg, 2.79 mmol) inEtOH (2.0 mL). The resulting mixture is heated at 110° C. in themicrowave for 1 hour. NaHCO₃ (246.5 mg, 2.93 mmol) is added, and thereaction is mixed well for 5 minutes. Then, the reaction is heated at110° C. in the microwave for 1 hour. The solvent is removed via reducedpressure, and the reaction is diluted with ethyl acetate (30 mL). Theorganic layer is washed with H₂O (3×10 mL), and the combined aqueouslayers are extracted with ethyl acetate (2×20 mL). The combined organicextracts are dried over Na₂SO₄, filtered, and purified by silica gelchromatography to give the title compound (29.5 mg, 0.068 mmol, 9.8%).¹H-NMR (CDCl₃), δ 0.87 (t, J=7.6 Hz, 6H), 1.86 (m, 4H), 2.60 (s, 3H),3.30 (m, 1H), 6.80 (s, 1H), 8.14 (s, 1H) ppm. ES-MS (m/z): calcd forC₁₃H₁₆F₃N₃ (M+H)⁺: 271.29. found: 272.2

B.8-(1-Ethyl-propyl)-6-methyl-3-(3-methyl-thiophen-2-yl)-2-trifluoromethyl-imidazo[1,2-b]pyridazine

To a dry 10 ml round bottom flask with reflux condenser containing8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine(300 mg, 1.11 mmol), 2-bromo-3-methyl-thiophene (216 mg, 1.22 mmol), andCs₂CO₃ (760 mg, 2.33 mmol) is added NMP (1.7 ml). The mixture isdegassed with bubbling N₂ for 15 min and Pd₂(dba)₃ (50.8 mg, 0.055 mmol)and PPh₃ (58.2 mg, 0.222 mmol) are added. The reaction mixture isstirred at 130° C. overnight. The mixture is cooled to rt, diluted withH₂O; and extracted with EtOAc (3×20 ml). The organic layers are dried(Na₂SO₄), filtered and purified by HPLC to give title compound (32 mg,0.087 mmol, 8%). 1H-NMR (CDCl₃), δ 0.93 (t, J=7.2 Hz, 6H), 1.91 (m, 4H),2.15 (s, 3H), 2.58 (s, 3H), 3.36 (m, 1H), 6.91 (s, 1H), 7.08 (d, J=5.3Hz, 1H), 7.55 (d, J=5.5 Hz, 1H) ppm. ES-MS (m/z): calcd for C₁₉H₂₀F₃N₃S(M+H)⁺: 367.44. found: 368.1.

Example 253 Preparation of3-[3-Chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

In a dry 25 mL round bottom flask,8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine(182 mg, 0.671 mmol),5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-¹H-[1,2,4]triazole (225 mg,0.805 mmol), KOAc (330.2 mg, 3.36 mmol), and TBAB (217 mg, 0.671 mmol)are dissolved in NMP (3 mL). The mixture is degassed with bubblingnitrogen for 20 minutes. Then, Pd(OAc)₂ (8 mg, 0.034 mmol) and TDBPP(20.4 g, 0.34 moles) are added. The reaction mixture is heated to 125°C. for 3 hours to give the title compound (125 mg, 0.267 mmol, 40%).¹H-NMR (CDCl₃), δ 0.88 (t, J=7.2 Hz, 6H), 1.87 (m, 4H), 2.537 (s, 3H),3.32 (m, 1H), 4.16 (s, 3H), 6.86 (s, 1H), 7.51 (s, 1H), 7.91 (s, 1H)ppm. ES-MS (m/z): calcd for C₂₀H₂₀ClF₃N₆S (M+H)⁺: 468.93. found: 469.2.

Example 254 Preparation of3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

A.8-(1-Ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

In a dry 25 mL round bottom flask,8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine(460 mg, 1.70 mmol) are dissolved in dry THF (3.5 mL) and cooled to −78°C. A solution of 2.5 M n-butyllithium in hexanes (748 μL, 1.87 mmol) isadded dropwise. The reaction mixture is stirred for 20 minutes at −78°C., then warmed to 0° C. for 15 minutes. A solution of 12 (453 mg, 1.79moles) in THF (2.0 mL) is added dropwise. The reaction is stirred for 15minutes at 0° C., and then warmed to room temp. The reaction is stirredovernight, and the solvent is removed via reduced pressure. The reactionmixture is redissolved in ethyl acetate (50 mL) and washed with a 1 Nsolution of Na₂S₂O₃ (2×20 mL). The aqueous layer is extracted with ethylacetate (2×40 mL). The combined organic extracts are dried with Na₂SO₄,filtered, and purified via silica gel chromatography to give the titlecompound (595 mg, 1.50 mmol, 88%). 1H-NMR (CDCl₃), δ 0.82 (t, J=8.0 Hz,6H), 1.83 (m, 4H), 2.64 (s, 3H), 3.27 (m, 1H), 6.82 (s, 1H) ppm. ES-MS(m/z): calcd for C₁₃H₁₅F₃₁N₃ (M+H)⁺: 397.18. found: 398.3.

B. 2,4-Dichloro-thiazole

In a 250 mL round bottom flask, 2,4-thiazolidine dione (12.5 g, 107mmol) is dissolved in phosphorousoxychloride (70 mL) and pyridine (8.5mL). The mixture is stirred under reflux for 3 hours and cooled to roomtemp. The reaction mixture is poured into ice water slowly and extractedwith dichloromethane. The combined organic extracts are dried withNa₂SO₄, filtered, and concentrated. The residue is purified via silicagel chromatography to give title compound (9.18 g, 59.6 mmol, 56%).¹H-NMR (CDCl₃), δ 7.01 (s, 1H) ppm.

C. 4-(4-Chloro-thiazol-2-yl)-morpholine

In a 75 mL dry pressure vessel, 2,4-dichloro-thiazole (500 mg, 3.2 mmol)and morpholine (560 μL, 6.4 mmol) are dissolved in dry THF (2.0 mL).Cs₂CO₃ (1.56 g, 4.8 mmol) is added, and the reaction vessel is sealed.The reaction mixture is heated to 110° C. overnight. Solvent is removedvia reduced pressure, and the crude reaction mixture is purified viasilica gel chromatography to give the title compound (597 mg, 2.92 mmol,91%). ¹H-NMR (CDCl₃), δ 3.45 (m, 4H), 3.79 (m, 4H), 6.31 (s, 1H) ppm.ES-MS (m/z): calcd for C₇H₉ClN₂OS (M+H)⁺: 204.68. found: 205.2.

D.3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine

In a dry 25 mL round bottom flask,8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine(250 mg, 0.630 mmol), 4-(4-chloro-thiazol-2-yl)-morpholine (194 mg,0.945 mmol), and Cs₂CO₃ (410 mg, 1.26 mmol) are dissolved in DMF. Themixture is degassed with bubbling nitrogen for 15 minutes. Then,Pd₂(dba)₃ (18 mg, 0.032 mmol) and PPh₃ (33 mg, 0.126 mmol) are added.The reaction mixture is heated to 130° C. overnight. The reaction iscooled to room temp., quenched with a solution of NH₄Cl sat? (20 mL),and extracted with Et₂O (3×50 mL). The combined organic extracts arewashed with brine (30 mL), dried with Na₂SO₄, filtered and concentrated.The residue is purified via reverse phase HPLC with a 30-80% gradient ofCH₃CN in 10 mM NH₄HCO₃/H₂O/5% CH₃CN (pH 10.0) to give the title compound(11 mg, 0.023 mmol, 4%). ¹H-NMR (CDCl₃), δ 0.86 (t, J=7.3 Hz, 6H), 1.84(m, 4H), 2.55 (s, 3H), 3.31 (m, 1H), 3.54 (dd, J=5.2, 4H), 3.84 (dd,J=5.2 Hz, 4H), 6.82 (s, 1H) ppm. ES-MS (m/z): calcd for C₂₀H₂₃ClF₃N₅OS(M+H)⁺: 473.95. found: 474.2.

Example 255 Preparation of{4-Chloro-5-[8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-dimethyl-amine

A. (4-Chloro-thiazol-2-yl)-dimethyl-amine

Using a procedure analogous to Example 254C, 2,4-dichloro-thiazole (500mg, 3.2 mmol) and dimethylamine (a 2.0 M solution in THF, 3 mL, 6.4mmol) are reacted to give the title compound (60 mg, 0.152 mmol, 15%).¹H-NMR (CDCl₃), δ 3.09 (s, 6H), 6.22 (s, 1H) ppm. ES-MS (m/z): calcd forC₅H₇ClN₂S (M+H)⁺: 162.64. found: 163.2.

B.{4-Chloro-5-[8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-dimethyl-amine

Using a procedure analogous to Example 254D,8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine(250 mg, 0.630 mmol) is coupled with(4-chloro-thiazol-2-yl)-dimethyl-amine (154 mg, 0.945 mmol) to providedesired product. ¹H-NMR (CDCl₃), δ 0.85 (t, J=7.4 Hz, 6H), 1.83 (m, 4H),2.55 (s, 3H), 3.16 (s, 6H), 3.31 (m, 1H), 6.81 (s, 1H) ppm. ES-MS (m/z):calcd for C₁₈H₂₁ClF₃N₅S (M+H)⁺: 431.91. found: 432.2.

Example A In Vivo Potency Assessment Using Ex Vivo Binding

To assess in vivo potency, a compound of the present invention isevaluated using ex vivo binding. Using the procedures as provided in D.R. Gehlert et al., EJP 509: 145-153 (2005), a compound is administeredto a rat via the oral route. The binding of ¹²⁵I-sauvagine to thecerebellum is then assessed ex vivo as described in Gehlert et al. Forexample, Example 199 provides an ED₅₀ result of 1.3 mg/kg.

Example B CRF1 Filter Binding Assay

The limitations of plasmid-based human CRF1 expression, in terms ofgenerating a recombinant cell line with sufficient receptor density todevelop a binding assay, are overcome by using a Phoenix retroviralexpression system licensed from Stanford. The stable HEK-hCRF1 cell lineis used to prepare membranes and binding reactions (200 μl) are set upas follows: 50 μl of ¹²⁵I-sauvagine (0.2 nM final), 50 μl compound and100 μl CRF1 membrane (25 μg/reaction). The reactions are incubated atroom temperature for 2 hours and then terminated by filtration throughpre-treated FB Millipore glass fiber filter plates (96 well). The platesare wash twice with ice-cold assay buffer (50 mM tris, 12.5 mM NaCl, 1mM EDTA, 10 mM MgCl₂, 0.05% BSA, pH 7.2), air dried over night andcounted with 100 μl Microscint 40 in a MicroBeta counter. Non-specificbinding (NSB) is determined in the presence of 0.5 μM non-labeledsauvagine. Triplicate determinations are typically run and the mediandata points plotted by Graph Pad Prism.

Using this assay, the claimed exemplified compounds of the presentinvention inhibit the binding of ¹²⁵I-Sauvagine (4 nM) inroller/adherent cells with a Ki (inhibition constant) below 1 μM. Forexample, Examples 102 and 199 exhibit a Ki of 4.92±0.57 nM and 9.98±0.72nM, respectively.

Example C CRF2 Filter Binding Assay

The limitations of plasmid-based human CRF2 expression, in terms ofgenerating a recombinant cell line with sufficient receptor density todevelop a binding assay, are overcome by using a Phoenix retroviralexpression system licensed from Stanford. The stable HEK-hCRF2 cell lineis used to prepare membranes and binding reactions (200 μl) are set upas follows: 50 ul of ¹²⁵I-sauvagine (0.2 nM final concentration), 50 μlcompound and 100 μl CRF2 membrane (25 μg/reaction). The reactions areincubated at room temperature for 2 hours and then terminated byfiltration through pre-treated FB Millipore glass fiber filter plates(96 well). The plates are washed twice with ice-cold assay buffer (50 mMtris, 12.5 mM NaCl, 1 mM EDTA, 10 mM MgCl₂, 0.05% BSA, pH 7.2), airdried over night and counted with 100 μl Microscint 40 in a MicroBetacounter. Non-specific binding (NSB) is determined in the presence of 0.5μM non-labeled sauvagine. Alternatively, compounds are evaluated using aScintillation Proximity assay. This assay is set up as follows: 50 ul of¹²⁵I-Sauvagine (0.2 nM final concentration), 50 μl compound ornon-labelled sauvagine (NSB) and 100 μl containing 250 μg wheat germagglutinin (WGA) SPA beads and CRF2 membrane (1.5 μg/reaction). Platesare incubated for 4-5 hours at room temperature and then centrifuged at200×g for 10 minutes. Bound radioactivity is assessed using a WallacTrilux scintillation counter. Binding is assessed typically usingtriplicate determinations and the median data points plotted by GraphPad Prism. Compounds are initially screened at a fixed concentrationand, if sufficient activity is noted, subsequent concentration-responsecurves are generated.

Compounds of the present invention are tested in the CRF2 binding assayand exhibit weak affinity for the CRF2 receptor. For example, Examples102 and 199 exhibit a percent inhibition at 50 μM of 9.0±2.6 and16.9±1.9, respectively. These results suggest that the compounds of thepresent invention are highly selective for the CRF1 receptor.

Example D Bioavailability and Pharmacokinetic Properties

The compounds of Formula I are antagonists of CRF1, and possesssurprisingly useful properties related to their pharmacokinetics andbioavailability.

The volume of distribution (Vdist) relates the amount of the drug in thebody to the concentration of the drug in the blood or plasma. The volumeof distribution refers to the fluid volume that would be required tocontain the total amount of the drug in the body at the sameconcentration as in the blood or plasma: Vdist=amount of drug in thebody/concentration of drug in blood or plasma (Goodman and Gillman's).For a 10 mg dose and a plasma concentration of 10 mg/L, the volume ofdistribution would be 1 liter. The volume of distribution reflects theextent to which the drug is present in the extravascular tissue. A largevolume of distribution reflects the tendency of a compound to bind tothe tissue components compared with plasma protein binding. In aclinical setting, Vdist can be used to determine a loading dose achievea steady state concentration.

To test for volume of distribution, Male Sprague Dawley rats (N=3) areadministered a single 3 mg/kg intravenous dose of compound. Multipleplasma samples are collected at time points from 0.08 to 24 hourspost-dose. The plasma samples are analyzed by LC/MS/MS to determine theplasma concentrations. Plasma pharmacokinetic calculations are performedto determine the pharmacokinetic parameters including Vdist and plasmaclearance (Clp).

An overwhelming majority of commercial CNS and cardiovascular drugsexhibit a human Vdist of <10 L/Kg. In comparison with CRF antagonistsCP154526 (Schulz et al., Proc. Natl. Acad. Sci. (USA), 93:10477 (1996))and NBI30775 (Chen et al., Drug Development Research, 65:216 (2005))which exhibit a rat Vdist of 114 L/Kg and 76 L/Kg, respectively,following a single intravenous dose, thiazole Examples 48 and 199 of thepresent invention exhibits a rat Vdist of only 9 and 2 L/Kg,respectively. Furthermore, thiophene Examples 88 and 39 of the presentinvention exhibit a rat Vdist of only 44 and 17 L/kg, respectively.

1.-10. (canceled)
 11. A compound of Formula I

wherein: R⁰ is hydrogen, halo, methyl or ethyl; R¹ and R³ areindependently methyl, methoxy, or trifluoromethyl; R² is selected fromthe group consisting of:

R⁴ is hydrogen, halo, or hydroxy; R^(5a) and R^(5b) are independentlyethyl or n-propyl; R⁶ at each occurrence is independently hydrogen,halo, cyano, (C₁-C₄)alkyl, trifluoromethyl, methoxy, or phenyl; R⁷ ishydrogen, halo, methyl, methoxy, dimethylamino,

R⁸ is selected from the group consisting of hydrogen, halo, cyano,(C₁-C₄)alkyl, R^(a)R^(b)N—, carbamyl, (C₁-C₂)alkoxy(C₁-C₂)alkyl,R¹¹—C(O)—,

R¹¹ is methoxy, methylamino, dimethylamino, or phenyl; R¹² is hydrogen,halo, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxydimethylamino, acetyl, or methylsulfonyl; R¹³ is hydrogen, methyl orhalo; R¹⁴ is hydrogen or hydroxy; R¹⁵ is methylthio, cyclopropyl,phenyl,

R^(a) is hydrogen, (C₁-C₅)alkyl, (C₃-C₅)cycloalkyl, methoxy(C₂-C₄)alkyl,acetyl, (C₁-C₂)alkylsulfonyl, (C₃)alkenyl, R¹⁵—(CH₂)n-, or (C₁-C₂)alkylsubstituted with cyano, formyl, vinyl, or ethynyl; R^(b) is hydrogen or(C₁-C₃)alkyl; X is —CH₂—, —CO—, —O—, —S— or —SO₂—; Y is —CH₂— or —O—; zis S or O; n is 1 or 2; Q is hydrogen or methyl; T is hydrogen ormethyl; J is methyl, trifluoroethyl, or tert-butyl; and M is methyl orhalo; or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 11 wherein R⁰ and R⁴ are hydrogen, R¹ and R³ aremethyl, and R^(5a) and R^(5b) are ethyl.
 13. The compound according toclaim 12, wherein R² is


14. The compound according to claim 13, wherein R⁸ is


15. The compound according to claim 14 which isN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholineor a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 14 which isN-{4-chloro-5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-thiazol-2-yl}-morpholine,hydrochloride salt.
 17. The compound according to claim 14 which is3-[4-bromo-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineor a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 14 which is3-[4-chloro-2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineor a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 14 which is3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazineor a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising the compound according to claim 11, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.
 21. A method of treatingalcohol withdrawal symptoms or alcohol dependence which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of the compound according to claim 11, or a pharmaceuticallyacceptable salt thereof.